Agent and method for maintaining or improving cerebral function using crude drug

Abstract

Provided is an agent for maintaining or improving cerebral function, the agent containing a crude drug selected from the leaf, fruit, or seed of Pipturus albidus.

Description

Agents and methods for maintaining or improving brain function using herbal medicines The present invention relates to agents and methods for maintaining or improving brain function using herbal medicines, promoting the repair of nerve cells or inducing neurogenesis, removing proteins that cause neurodegenerative diseases and accumulate in the brain, or treating or preventing neurodegenerative diseases, and to foods and medicines containing such agents. The number of dementia patients is rapidly increasing worldwide due to the aging of society and the westernization of lifestyles and eating habits. The social costs of medical care and nursing care, as well as the economic losses due to the reduced labor force of patients and their families, are enormous, and have become a major social problem. Representative dementias include Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies. All of these are neurodegenerative diseases, and dementia caused by these is called degenerative dementia. In these diseases, it is believed that certain proteins aggregate and accumulate in the nervous system, which causes the death of nerve cells, resulting in the onset of dementia. Specifically, Aβ and tau accumulate in the brain in Alzheimer's disease, tau and TDP-43 in frontotemporal dementia, and α-synuclein in dementia with Lewy bodies (Non-Patent Document 1: Spires-Jones et al., Acta Neuropathol., (2017), 134[2]:187-205). Efforts are underway to develop anti-dementia drugs that suppress the production of these causative proteins or remove them from the brain. Candidates for such anti-dementia drugs include Aβ-producing enzyme (β-secretase and γ-secretase) inhibitors (Non-Patent Document 2: Luo et al., Cell & Biosci., (2022), 12:2), Aβ vaccines (Non-Patent Document 3: Valiukas et al., Vaccines, (2022), 10[9]:1527), and Aβ antibodies (Non-Patent Document 4: Song et al., Transl. Neurodegener., (2022), 11:18) for Alzheimer's disease, and tau vaccines (Non-Patent Document 5: Medina, Int. J. Mol. Sci., (2018), 19[4]:1160) and tau antibodies (Non-Patent Document 6: Ji et al., Drugs, (2021), 81

[0010] For dementia with Lewy bodies, alpha-synuclein vaccines and alpha-synuclein antibodies (Non-Patent Document 7: Alzforum website, FBRI LLC, search result for alpha-synuclein Target, https: / / www.alzforum.org / therapeutics / search?fda_statuses=&target_types%5B%5D=33416&therapy_types=&conditions=&keywords-entry=&keywords=, searched December 2022) have been considered. However, most of the anti-dementia drug candidates developed to date have failed in clinical trials targeting dementia patients, as the expected efficacy has not been confirmed (Non-Patent Document 8: Asher et al., Life Sciences, (2022), 306:120861). The leaves of the Hawaiian native herb Mamaki (Pipturus albidus) are used as an ingredient in a popular herbal tea in Hawaii. In Hawaii, Mamaki, especially its fruit, has a history of being used as a natural folk medicine to regulate blood sugar, blood pressure, and cholesterol levels, relieve stress and fatigue, and reduce inflammation (Non-Patent Document 9: Rafii et al., Alzheimers Dement., (2022), 1-7). However, it is not known whether it is effective against dementia. Spires-Jones et al., Acta Neuropathol., (2017), 134[2]:187-205Luo et al., Cell & Biosci., (2022), 12:2Valiukas et al., Vaccines, (2022), 10[9]:1527Song et al., Transl. Neurodegen., (2022), 11:18Medina, Int. J. Mol. Sci., (2018), 19[4]:1160Ji et al., Drugs, (2021), 81

[0010] :1135-1152AlzforumウウブトFBRI LLC, alpha-synuclein Details of target at https: / / www.alzforum.org / therapeutics / search?fda_statuses=&target_types%5B%5D=33416&therapy_types=&conditions=&keywords-entry=&keywords=, 2022 Asher et al., Life Sciences, (2022), 306:120861Rafii et al., Alzheimers Dement., (2022), 1-7Chun et al., Native Hawaiian Medicines, First People's Productions Honolulu, (1994), 216-217Afzal et al., Molecules, (2022), 27

[0021] :7604Payne et al., Biomolecules, (2022), 12[3]:371Li et al., Neuroscience, (2009), 159[4]:1208-15Yoo et al., Phytother Res. 24[7]:1065-70Colucci-D'Amato et al., Int. J. Mol. Sci., (2020), 21

[0020] :7777Horgusluoglu et al., Am. J. Med. Gene. B. Neuropsychiatr. Genet., (2017), 174[1]:93-112Socala et al., Int. J. Mol. Sci., (2020), 22[1]:107Gao et al., Drug Des. Devel. Ther., (2020), 14:1705-1716Singh et al., Oxid. Med. Cell Longev., (2020), 2020:6571484Liu et al., Drug Des. Devel. Ther., (2020), 14:51-60Tahir et al., Biomed. Pharmacother., (2021), 137:111253Xu et al., Behav. Brain Res., (2014), 264:173-80Sun et al., J. Neuroinflammation, (2021), 18[1]:131Moghbelinejad et al., Toxicol Lett., (2014), 224[1]:108-13Umeda et al., Am. J. Pathol., (2013), 183[1]:211-25Umeda et al., Ann. Clin. Transl. Neurol., (2015), 2[3]:241-55Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. U.S.A., (1997), 94

[0024] :13287-92Van Dam et al., Eur. J. Neurosci., (2003), 17[2]:388-96Umeda et al., Front. Neurosci., (2021), 15:763476Lee et al., Proc. Natl. Acad. Sci. U.S.A., (2002), 99

[0013] :8968-73Umeda et al., Int. J. Mol. Sci., (2021), 22:8453Liu et al., Neuron, (2016), 90[3]:521-534Hatanaka et al., Biomedicines, (2022), 10[5]:1080. The problem to be solved by the present invention is to provide a new means for maintaining or improving brain function, promoting the repair of nerve cells or inducing neurogenesis, removing proteins that cause neurodegenerative diseases and accumulate in the brain, or treating or preventing neurodegenerative diseases. As a result of extensive research, the inventors have found that herbal medicines selected from the leaves, fruits, and seeds of Mamaki, each in a specific form, have various effects such as maintaining or improving brain function, promoting the repair of nerve cells or inducing neurogenesis, removing proteins that cause neurodegenerative diseases that accumulate in the brain, or treating or preventing neurodegenerative diseases, and have completed the present invention. That is, the gist of the present invention relates to, for example, the following. [Item 1] An agent for maintaining or improving brain function, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 2] The agent for maintaining or improving brain function according to Item 1, wherein the brain function is a cognitive function. [Item 3] An agent for promoting the repair of nerve cells or inducing neurogenesis, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 4] An agent for removing proteins that cause neurodegenerative diseases and accumulate in the brain, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 5] The agent according to Item 4, wherein the neurodegenerative disease causative protein is one or more proteins selected from amyloid beta (Aβ), tau, α-synuclein, TDP-43, FUS / TLS, polyglutamine, a protein produced by repeat-associated non-ATG (RAN) translation, prion, and SOD-1. [Item 6] A therapeutic or preventive agent for neurodegenerative diseases, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 7] The agent according to Item 6, wherein the neurodegenerative disease is degenerative dementia. [Item 8] The agent according to Item 7, wherein the degenerative dementia is one or more types of dementia selected from Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and dementia caused by Parkinson's disease or amyotrophic lateral sclerosis. [Item 9] The agent according to any one of Items 1 to 8, wherein the herbal medicine selected from the leaves, fruits, and seeds of Mamaki is a crushed product and / or extract of the leaves and / or fruits and / or seeds of Mamaki. [Item 10] The agent according to any one of Items 1 to 9, wherein the herbal medicine is administered to a subject in an amount of 0.01 mg to 10 g per day. [Item 11] A food comprising the agent according to any one of items 1 to 10. [Item 12] A medicine comprising the agent according to any one of items 1 to 10. [Item 13] A method for maintaining or improving a subject's brain function, comprising administering a herbal medicine selected from the leaves, fruits, and seeds of Mamaki to a subject in need thereof. [Item 14] The method according to item 13, wherein the brain function is a cognitive function. [Item 15] A method for promoting the repair of nerve cells or inducing neurogenesis in a subject, comprising administering a herbal medicine selected from the leaves, fruits, and seeds of Mamaki to a subject in need thereof. [Item 16] A method for removing a neurodegenerative disease-causing protein that accumulates in the brain of a subject, comprising administering to a subject in need thereof a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 17] The method according to Item 16, wherein the neurodegenerative disease causative protein is one or more proteins selected from amyloid beta (Aβ), tau, α-synuclein, TDP-43, FUS / TLS, polyglutamine, a protein produced by repeat-associated non-ATG (RAN) translation, prion, and SOD-1. [Item 18] A method for treating or preventing a neurodegenerative disease in a subject, comprising administering to a subject in need thereof a herbal medicine selected from the leaves, fruits, and seeds of Mamaki. [Item 19] The method according to Item 18, wherein the neurodegenerative disease is degenerative dementia. [Item 20] The method according to Item 19, wherein the degenerative dementia is one or more types of dementia selected from Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and dementia caused by Parkinson's disease or amyotrophic lateral sclerosis. [Item 21] The method according to any one of Items 13 to 20, wherein the herbal medicine selected from the leaves, fruits, and seeds of Mamaki is a crushed product and / or an extract of the leaves and / or fruits and / or seeds of Mamaki. [Item 22] The method according to any one of Items 13 to 21, wherein the herbal medicine is administered to the subject in an amount of 0.01 mg to 10 g per day. According to the present invention, by using herbal medicines selected from the leaves, fruits, and seeds of Mamaki, each in a specified form, a new means is provided for maintaining or improving brain function, promoting the repair of nerve cells or inducing neurogenesis, removing proteins that cause neurodegenerative diseases and accumulate in the brain, or treating or preventing neurodegenerative diseases. Figure 1 is a graph showing the results of the Morris water maze test for Tau784 mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) for one month, compared with Tau784 mice ("Tg" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as control. Figure 1A is a graph showing the results for the 1000 μg / day and 100 μg / day dose groups, and Figure 1B is a graph showing the results for the 30 μg / day dose group. Figure 2 shows tau pathology in the entorhinal cortex of Tau784 mice that were orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month ("Tau784+Leaf-ext" in the table), compared with control Tau784 mice that were administered water ("Tau784" in the table). Figure 2A shows photographs showing the staining results for phosphorylated tau and tau oligomers, and Figure 2B shows graphs showing the quantification of the staining intensity of each photograph. 3 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Tau784 mice ("Tau784+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with control Tau784 mice ("Tau784" in the table) and non-transgenic mice ("Non-Tg" in the table). Figure 3A shows photographs showing the results of synaptophysin staining, and Figure 3B shows graphs showing the quantification of the staining intensity of each photograph. Figure 4 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of Tau784 mice ("Tau784+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with control Tau784 mice ("Tau784" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water. Figure 4A is a photograph showing the staining results of activated microglia, and Figure 4B is a graph showing the number of positive cells in each photograph.5 is a graph showing the results of the Morris water maze test of APP23 mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with APP23 mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered with water as a control. FIG. 6 is a graph showing amyloid pathology in the cerebral cortex and hippocampus of APP23 mice ("APP23+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with APP23 mice ("APP23" in the table) administered with water as a control. FIG. 6A is a photograph showing the staining results of amyloid deposits and Aβ oligomers, and FIG. 6B is a graph showing the results of quantifying the staining intensity of each photograph. FIG. 7 is a diagram showing synaptophysin pathology in the hippocampal CA2 / 3 region of APP23 mice (in the table, "APP23+Leaf-ext") orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with APP23 mice (in the table, "APP23") and non-genetically modified mice (in the table, "Non-Tg") administered water as a control. FIG. 7A is a photograph showing the staining results of synaptophysin, and FIG. 7B is a graph showing the results of quantifying the staining intensity of each photograph. Figure 8 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of APP23 mice ("APP23+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with APP23 mice ("APP23" in the table) administered water as control and non-genetically modified mice ("Non-Tg" in the table). Figure 8A is a photograph showing the staining results of activated microglia, and Figure 8B is a graph showing the number of positive cells in each photograph. FIG. 9 is a graph showing the results of a Morris water maze test in Huα-Syn(A53T) mice ("Tg+Leaf-ext" in the table) that were orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with Huα-Syn(A53T) mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) that were administered water as controls.Figure 10 shows α-synuclein pathology in the hippocampus (HC) and entorhinal cortex (EC) of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) administered water as a control. Figure 10A is a photograph showing the staining results for phosphorylated α-synuclein, and Figure 10B is a graph showing the quantification of the staining intensity of each photograph. Figure 11 shows α-synuclein pathology in the hippocampus (HC) and entorhinal cortex (EC) of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) administered water as a control. Figure 11A shows photographs showing the staining results of α-synuclein oligomers, and Figure 11B shows graphs showing the quantification of the staining intensity of each photograph. 12 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. FIG. 12A is a photograph showing the results of staining for synaptophysin, and FIG. 12B is a graph showing the results of quantifying the staining intensity of each photograph. FIG. 13 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. FIG. 13A is a photograph showing the staining results of activated microglia, and FIG. 13B is a graph showing the number of positive cells in each photograph.FIG. 14 is a graph showing the results of the Morris water maze test of C9-500 mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with C9-500 mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. FIG. 15 is a graph showing the pathology caused by a mutation in the C9orf72 gene in the prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with C9-500 mice ("C9-500" in the table) administered water as a control. Figure 15A is a photograph showing the staining results of RNA G-quadruplex, poly-GA, poly-GP, and phosphorylated TDP-43, and Figure 15B is a graph showing the results of quantifying the staining intensity of each photograph. Figure 16 is a diagram showing double-stranded RNA-dependent protein kinase (PKR) pathology in the hippocampal CA2 / 3 region prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with C9-500 mice ("C9-500" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as a control. FIG. 16A is a photograph showing the staining results of phosphorylated PKR, and FIG. 16B is a graph showing the results of quantifying the staining intensity of each photograph. FIG. 17 is a diagram showing synaptophysin pathology in the hippocampal CA2 / 3 region of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with C9-500 mice ("C9-500" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. FIG. 17A is a photograph showing the staining results of synaptophysin, and FIG. 17B is a graph showing the results of quantifying the staining intensity of each photograph.Figure 18 shows microglial pathology in the prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with control C9-500 mice ("C9-500" in the table) administered water and non-transgenic mice ("Non-Tg" in the table). Figure 18A is a photograph showing the staining results of activated microglia, and Figure 18B is a graph showing the number of positive cells in each photograph. FIG. 19 is a graph showing the results of a Morris water maze test in Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, in comparison with Tau784 mice (respectively "Tg" in the table) and non-genetically modified mice (respectively "Non-Tg" in the table) administered water as control. FIG. 20 shows tau pathology in the entorhinal cortex of Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice (respectively "Tg+Leaf-pwd" in the table) administered water as a control. FIG. 20A is a photograph showing the staining results of phosphorylated tau and tau oligomers, and FIG. 20B is a graph showing the results of quantifying the staining intensity of each photograph. FIG. 21 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Tau784 mice (represented by “Tg+Leaf-ext”, “Tg+Leaf-pwd”, and “Tg+Fruit-pwd” in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, in comparison with control Tau784 mice (represented by “Tau784” in the table) and non-genetically modified mice (represented by “Non-Tg” in the table) administered water.Figure 21A is a photograph showing the results of staining for synaptophysin, and Figure 21B is a graph showing the results of quantifying the staining intensity of each photograph. Figure 22 shows BDNF expression in the cerebral cortex (CTX) of Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice ("Tau784" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. FIG. 22A is a photograph showing the staining results of BDNF, and FIG. 22B is a graph showing the results of quantifying the staining intensity of each photograph. FIG. 23 shows the neurogenesis levels in the dentate gyrus (DG) and substantia nigra (SN) of Huα-Syn(A53T) mice (in the table, "αSyn-Tg+Fruit-pwd") orally administered a simple crushed powder (including seeds) of mamaki fruit at a dose of 30 μg / day for one month, compared with Huα-Syn(A53T) mice (in the table, "αSyn-Tg") and non-transgenic mice (in the table, "Non-Tg"). FIG. 23A shows immunofluorescent staining photographs of BrdU (red) and doublecortin (DCX) (green). Double positive cells (yellow) positive for both BrdU (red) and DCX (green) were considered to be newborn neurons. Figure 23B is a graph showing the results of quantifying the number of double positive cells (yellow) in each photograph. Figure 24 is a graph showing the results of the Morris water maze test of Tau784 mice orally administered a mixture of 0.087 μg catechin, 0.036 μg chlorogenic acid, and 0.123 μg rutin ("Tg+3 polyphenol mixture" in the table) or 0.087 μg catechin alone ("Tg+chatechin" in the table) for one month, compared with Tau784 mice administered water as a control ("Tg" in the table) and non-transgenic mice ("Non-Tg" in the table). The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments, and can be embodied in any form without departing from the spirit of the present invention. [overview] As mentioned above, the reason why most of the anti-dementia drugs that have been studied so far have failed is thought to be that the drugs were administered too late and that the wrong molecules were targeted, apart from the problem of side effects. It has been shown that Aβ accumulation in the brain begins more than 20 years before the onset of Alzheimer's disease, and tau accumulation begins about 10 years before that. Aβ accumulates, tau accumulates, nerve cells begin to die, and then dementia finally develops. In other words, by the time dementia develops, many nerve cells have already died. If Aβ or tau is to be removed, it is meaningless unless it is done before nerve cells begin to die. In other words, the role of drugs that target Aβ and tau is not treatment but prevention. In addition, it was previously thought that insoluble protein aggregates such as senile plaques and neurofibrillary tangles (accumulation of aggregated tau) kill nerve cells, causing the onset of the disease. However, recently, it is thought that soluble oligomers formed in the previous stage impair the function of nerve cells, causing dementia. Therefore, in order to prevent dementia, it is necessary to remove oligomers of the causative protein. From the viewpoint of prevention, it is desirable that a single drug can act on oligomers of various causative proteins, rather than Aβ-specific, tau-specific, or α-synuclein-specific. Furthermore, it is also necessary that the drug can repair nerve cells damaged by oligomers and restore brain function. In addition, since the prevention of dementia is a long-term process, it is desirable that the preventive drug is safe and inexpensive, and if possible, can be taken non-invasively by the patient without the help of a doctor. As described above, there are many requirements for a preventive drug for dementia, and it is difficult to achieve this with a drug consisting of a single ingredient. In addition, if all middle-aged and elderly people were to take the drug for a long period of time to prevent dementia, the medical economy would eventually collapse. In order to solve such problems, the inventors have focused on herbal medicines that have been used in naturopathy and traditional Chinese medicine, which have a long history. If there are herbal medicines that are effective in improving cognitive function, middle-aged and elderly people can obtain them at their own discretion without having to see a doctor, and by taking them in addition to meals, they can work to prevent dementia in their daily lives. Therefore, the present inventors have conducted extensive research and found that herbal medicines selected from the leaves, fruits, and seeds of Mamaki have various effects such as maintaining or improving brain function, promoting the repair of nerve cells or inducing neurogenesis, removing proteins that cause neurodegenerative diseases and accumulate in the brain, and treating or preventing neurodegenerative diseases. The present invention is based on such findings. That is, according to one aspect of the present invention, there is provided an agent for maintaining or improving brain function, an agent for promoting the repair of nerve cells or inducing neurogenesis, an agent for removing proteins that cause neurodegenerative diseases and accumulate in the brain, or an agent for treating or preventing neurodegenerative diseases (these may be collectively referred to as the "agent of the present invention" as appropriate), which contains a herbal medicine selected from the leaves, fruit, and seeds of Mamaki. Furthermore, according to one aspect of the present invention, a food product containing the agent of the present invention is provided (which may be appropriately referred to as the "food product of the present invention"). Furthermore, according to one aspect of the present invention, there is provided a medicine comprising the agent of the present invention (which may be appropriately referred to as the "medicine of the present invention"). Furthermore, according to one aspect of the present invention, there is provided a method for maintaining or improving brain function, a method for promoting the repair of nerve cells or inducing neurogenesis, a method for removing a neurodegenerative disease-causing protein that accumulates in the brain, or a method for treating or preventing a neurodegenerative disease (these may be collectively referred to as the "method of the present invention" as appropriate), which comprises administering to a subject one or more of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki, the agent of the present invention, the food of the present invention, and the medicine of the present invention. [Mamaki] According to one embodiment, the agent of the present invention contains a herbal medicine selected from the leaves, fruits, and seeds of mamaki. As mentioned above, the leaves of mamaki (Pipturus albidus), a herb native to Hawaii, are used as an ingredient in a popular herbal tea in Hawaii. In Hawaii, mamaki, especially its fruit, has a history of being used as a natural folk medicine to regulate blood sugar levels, blood pressure, and cholesterol levels, relieve stress and fatigue, and reduce inflammation (Non-Patent Document 9: Rafii et al., Alzheimers Dement., (2022), 1-7). However, it is not known whether it is effective against dementia. Three polyphenols, (+)-catechin, chlorogenic acid, and rutin, have been identified as major components of mamaki leaves (Non-Patent Document 10: Chun et al., Native Hawaiian medicines, First People's Productions Honolulu, (1994), pp. 216-217). The catechin and rutin contents of mamaki leaves are significantly higher than those of other commercially available tea leaves (Non-Patent Document 10). These polyphenols have been suggested to have beneficial effects on mouse models and humans with neurodegenerative diseases. Catechins are a type of flavonoid, consisting of catechin itself and its derivatives, and are abundant in tea leaves. They exhibit anti-inflammatory and antioxidant effects by blocking cytokine production and inflammatory pathways, chelating metal ions, and scavenging free radicals (Non-Patent Document 11: Afzal et al., Molecules, (2022), 27

[0021] :7604; and Non-Patent Document 12: Payne et al., Biomolecules, (2022), 12[3]:371). Catechins, especially epigallocatechin-3-gallate, have been shown to inhibit Aβ production, tau phosphorylation, and amyloid protein aggregation, thereby preventing cognitive decline in AD and PD (Non-Patent Documents 11 and 12 above). Furthermore, it has been reported that oral administration to mice increases the expression of brain-derived neurotrophic factor (BDNF) and neurogenesis (Non-Patent Document 13: Li et al., Neuroscience, (2009), 159[4]:1208-15; and Non-Patent Document 14: Yoo et al., Phytother Res., (2010), 24[7]:1065-70). BDNF and neurogenesis are important for brain repair and regeneration (Non-Patent Document 15: Colucci-D'Amato et al., Int. J. Mol. Sci., (2020), 21

[0020] :7777: and Non-Patent Document 16: Horgusluoglu et al., Am. J. Med. Gene. B. Neuropsychiatr. Genet., (2017), 174[1]:93-112). Chlorogenic acid, also known as 5-O-caffeoylquinic acid, is found in large amounts in coffee beans. It has a variety of beneficial health effects, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, cardioprotective, chemopreventive, antidiabetic, and anti-obesity effects, and it has been suggested that regular intake of chlorogenic acid reduces the risk of neurodegenerative diseases and improves cognitive function (Non-Patent Document 17: Socala et al., Int. J. Mol. Sci., (2020), 22[1]:107). Oral administration to AD and PD model mice has been shown to improve memory and motor function (Gao et al., Drug Des. Devel. Ther., (2020), 14:1705-1716; and Singh et al., Oxid. Med. Cell Longev., (2020), 2020:6571484), and oral administration to a rat model of cerebral ischemia / reperfusion has been shown to promote the expression of BDNF and nerve growth factor (NGF) (Liu et al., Drug Des. Devel. Ther., (2020), 14:51-60). Rutin is a member of the flavonol subtype of flavonoids and is found in various plants. It exhibits anti-inflammatory, antioxidant, and neuroprotective effects (Non-Patent Document 21: Tahir et al., Biomed. Pharmacother., (2021), 137:111253). When orally administered to AD model mice, it reduces Aβ and tau oligomers and improves cognitive function (Non-Patent Document 22: Xu et al., Behav. Brain Res., (2014), 264:173-80; and Non-Patent Document 23: Sun et al., J. Neuroinflammation, (2021), 18[1]:131). In addition, it has been reported that intraperitoneal administration of rutin to rats injected with Aβ increases BDNF expression (Non-Patent Document 24: Moghbelinejad et al., Toxicol Lett., (2014), 224[1]:108-13). As described above, the three polyphenols contained in the leaves of Mamaki, namely catechin, chlorogenic acid, and rutin, have been suggested to have effects such as improving cognitive function. However, the effects of improving cognitive function, etc. on the leaves and fruit of Mamaki are completely unknown. Therefore, as described in detail in the Examples below, the inventors separated the leaves and fruits (including seeds) from commercially available dried Mamaki tea leaves, prepared hot water extracts and simple crushed powders of each, and investigated the effects on cognitive function and neuropathology using four types of degenerative dementia model mice. First, Tau784 mice were used as a model of frontotemporal dementia-tau (FTD-Tau) (Umeda et al., Am. J. Pathol., (2013), 183[1]:211-25; and Umeda et al., Ann. Clin. Transl. Neurol., (2015), 2[3]:241-55) and were administered with a hot water extract of Mamaki leaves (Leaf-ext) at doses of 1000 μg / day, 100 μg / day, and 30 μg / day for one month (Example 1). As a result, significant improvements were observed at all doses in cognitive function (Figure 1), tau pathology (Figure 2), synaptophysin pathology (Figure 3), and microglial pathology (Figure 4). In particular, when administered at doses of 1000 μg / day and 100 μg / day, each pathology was improved to the same level as in non-transgenic littermates. In addition, APP23 mice (Non-Patent Document 27: Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. USA, (1997), 94

[0024] :13287-92; Non-Patent Document 28: Van Dam et al., Eur. J. Neurosci., (2003), 17[2]:388-96; and Non-Patent Document 29: Umeda et al., Front. Neurosci., (2021), 15:763476) were used as a model of Alzheimer's disease (AD) and were administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month (Example 2). As a result, cognitive function (Figure 5), amyloid pathology (Figure 6), synaptophysin pathology (Figure 7), and microglial pathology (Figure 8) were all improved to levels equivalent to or close to those of non-transgenic littermates. In addition, Huα-Syn (A53T) mice (Non-Patent Document 30: Lee et al., Proc. Natl. Acad. Sci. USA, (2002), 99

[0013] : 8968-73; and Non-Patent Document 31: Umeda et al., Int. J. Mol. Sci., (2021), 22: 8453) were used as a model of dementia with Lewy bodies (DLB), and a hot water extract of Mamaki leaves (Leaf-ext) was administered at a dose of 100 μg / day for one month (Example 3). As a result, each pathology was improved to a level equivalent to or close to that of non-transgenic mice of the same litter for cognitive function (Figure 9), synuclein pathology (Figures 10 and 11), synaptophysin pathology (Figure 12), and microglial pathology (Figure 13). In addition, C9-500 mice (Liu et al., Neuron, (2016), 90[3]:521-534; and Hatanaka et al., Biomedicines, (2022), 10[5]:1080) were used as a model of frontotemporal dementia-TDP (FTD-TDP), and a hot water extract of Mamaki leaves (Leaf-ext) was administered at a dose of 100 μg / day for one month (Example 4). As a result, cognitive function (Figure 14), pathology caused by mutations in the C9orf72 gene (Figure 15), double-stranded RNA-dependent protein kinase (PKR) pathology (Figure 16), synaptophysin pathology (Figure 17), and microglial pathology (Figure 18) were all improved to levels equivalent to or close to those of non-transgenic littermates. These results suggest that mamaki leaves have the effect of improving cognitive function and various associated pathologies. In addition, Tau784 mice (Non-Patent Documents 25 and 26) were used as a model of frontotemporal dementia-tau (FTD-Tau), and the hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) were administered at a dose of 30 μg / day for one month (Example 5). As a result, significant improvements were observed for all preparations in cognitive function (Figure 19), tau pathology (Figure 20), synaptophysin pathology (Figure 21), and BDNF expression (Figure 22). In particular, the simply crushed powder of Mamaki leaves (Leaf-pwd) and the simply crushed powder of fruits (including seeds) (Fruit-pwd) improved each pathology to a level equivalent to or close to that of non-transgenic littermates. In particular, the simple crushed powder of mamaki fruit (including seeds) (Fruit-pwd) surprisingly enhanced the cognitive function of Tau784 mice to a level even higher than that of non-transgenic littermates. These results suggest that crushed mamaki leaves and fruits (including seeds) have a far superior effect on improving cognitive function and various pathologies than extracts. In addition, using Huα-Syn(A53T) mice (Non-Patent Documents 30 and 31 above) as a model of dementia with Lewy bodies (DLB), simple crushed powder of mamaki fruit (including seeds) (Fruit-pwd) was administered at a dose of 100 μg / day for one month (Example 6). As a result, the neurogenesis level in the dentate gyrus (DG) and substantia nigra (SN) of Huα-Syn(A53T) mice was surprisingly improved to a level far exceeding that of non-transgenic littermates. These results suggest that crushed mamaki fruit (including seeds) has the effect of promoting brain rejuvenation through neuronal repair and regeneration. In addition, the following experiment was conducted to verify whether the cognitive function improving effect and various pathological improving effect of the leaves and fruits (including seeds) of Mamaki are due to the three polyphenols contained in the leaves of Mamaki, namely, catechin, chlorogenic acid, and rutin. That is, Tau784 mice (Non-Patent Documents 25 and 26) were used as a model of frontotemporal dementia-tau (FTD-Tau), and a mixture of catechin, chlorogenic acid, and rutin equivalent to the amount contained in 30 μg of simply crushed powder of Mamaki fruit (including seeds), or catechin alone, was administered for one month. As a result, the cognitive function improving effect of these catechin / chlorogenic acid / rutin mixtures and catechin alone was far inferior to that of non-genetically modified mice of the same litter and was incomplete. Therefore, it is clear that the various effects of the hot water extract of Mamaki leaves (Leaf-ext), the simply crushed powder of the leaves (Leaf-pwd), and the simply crushed powder of the fruit (including seeds) (Fruit-pwd) described above are not solely due to the three types of polyphenols mentioned above, but rather are largely due to the contribution of other unknown components contained in Mamaki. [Form of herbal medicine] According to one embodiment, the leaves, fruits, and seeds of mamaki may be used alone, the fruits of mamaki may be used alone, the seeds of mamaki may be used alone, or two or three of the leaves, fruits, and seeds of mamaki may be used in combination. The leaves and / or fruits and / or seeds of Mamaki may be used in any form, including, but not limited to, the leaves and / or fruits and / or seeds of Mamaki as is, or in the form of crushed material and / or extract. Specifically, when a crude drug selected from the leaves, fruits, and seeds of Mamaki is made into a crushed product such as crushed powder, the processing conditions are not particularly limited, but are, for example, as follows. First, the crude drug is subjected to a drying process. The conditions of the drying process are not limited, and various known conditions may be used. Examples include drying at a temperature of 0 to 100°C, such as natural drying or heat drying. Next, the dried crude drug is subjected to a crushing process. The means of the crushing process are also not limited, and various known means may be used. Examples include a manual crushing method and crushing using a crusher such as a wet crushing method or a dry crushing method. The crushed crude drug obtained may be used as it is, or may be passed through a sieve to obtain a powder with a particle size controlled to a predetermined value or less. For example, the particle size may be adjusted by using a sieve with an opening size of 0.02 mm to 20 mm. In addition, when the herbal medicine selected from the leaves, fruits, and seeds of Mamaki is made into an extract form, the processing conditions are not particularly limited, but for example, the herbal medicine may be optionally subjected to drying and / or crushing processing, and then an extraction solvent may be added to perform extraction. Specifically, for example, 1 to 100 parts by mass of the extraction solvent may be added to 1 part by mass of the dried and crushed herbal medicine, and the mixture may be held for, for example, 0.1 to 100 hours to perform extraction. The extraction solvent is also not particularly limited, and various known solvents may be used, examples of which include water and hydrophilic organic solvents such as ethanol. Extraction using the extraction solvent may be performed at room temperature or with heating. For example, when heating with water, the crushed material may be heated at 30 to 100°C after adding hot water. In addition, the extraction efficiency may be increased by combining stirring, ultrasonication, heating and refluxing, etc., as necessary. After the extraction is completed, the liquid component and the solid component are separated by manual labor or filtration or other means. The separated liquid component may be used as an extract. In either case, the solvent may be evaporated and concentrated before use as necessary. [Action of the agent] According to one embodiment, the agent of the present invention is an agent for maintaining or improving brain function. In the present invention, "maintaining or improving brain function" means, but is not limited to, maintaining or improving cognitive function and / or motor function. In the present invention, maintaining or improving "cognitive function" means, but is not limited to, preventing the occurrence of abnormalities such as mild forgetfulness, memory impairment seen in dementia, disorientation, impaired judgment / comprehension, impaired executive function, apraxia / agnosia / aphasia, or improving such abnormalities. In the present invention, maintaining or improving "motor function" means, but is not limited to, preventing the occurrence of abnormalities such as a decline in motor function due to aging, parkinsonism such as tremors, muscular rigidity, impaired postural reflexes, akinesia and hypokinesia seen in Parkinson's disease and the like, involuntary movements seen in Huntington's disease and the like, coordination disorders seen in spinocerebellar degeneration and the like, and muscle weakness seen in amyotrophic lateral sclerosis and the like, or improving such abnormalities. The effect of the agent of the present invention in maintaining or improving brain function can be evaluated, for example, as shown in the Examples described below, by administering the agent to a model animal that develops brain pathology and then subjecting the animal to a cognitive function test such as the Morris water maze test or a motor function test such as a rotarod test, or by staining and observing brain slices. According to one embodiment, the agent of the present invention is an agent for promoting repair of nerve cells or inducing neurogenesis. In the present invention, "promoting repair of nerve cells" includes, but is not limited to, recovery of the number and function of decreased synapses, recovery of decreased nerve cell function, and enhanced expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which promote the maintenance and recovery of the functions of synapses and nerve cells and protect nerve cells from various stresses. In the present invention, "induction of neurogenesis" means, but is not limited to, inducing the new emergence of immature nerve cells that actively synthesize DNA. Indicators of DNA synthesis include active incorporation of exogenously administered nucleic acid analogs such as BrdU, and expression of doublecortin as a marker of immature nerve cells. The effect of the agent of the present invention in promoting the repair of nerve cells or inducing neurogenesis can be evaluated by administering the agent to an animal model that develops dementia or brain pathology and then observing the induction of expression of brain-derived neurotrophic factor (BDNF), or by staining brain sections and observing newborn neurons, as shown in the Examples described later. According to one embodiment, the agent of the present invention is an agent for removing a neurodegenerative disease causative protein that accumulates in the brain. In the present invention, the term "neurodegenerative disease causative protein" refers to a protein that is identified or presumed to be a causative substance of dementia. Examples include, but are not limited to, one or more proteins selected from amyloid beta (Aβ), tau, α-synuclein, TDP-43, FUS / TLS, polyglutamine, proteins produced by RAN (repeat-associated non-ATG) translation, prion, SOD-1, and the like. The effect of the agent of the present invention in maintaining or improving brain function can be evaluated, for example, by administering the agent to a model animal that develops dementia and then staining and observing brain sections, as shown in the Examples described below. According to one embodiment, the agent of the present invention is a therapeutic or prophylactic agent for neurodegenerative diseases. In the present invention, the term "neurodegenerative disease" refers to, but is not limited to, a neurodegenerative disease in which any of the above-mentioned neurodegenerative disease causative proteins accumulate in the brain in the present specification. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease (Aβ, tau), frontotemporal dementia (tau, TDP-43, FUS / TLS), dementia with Lewy bodies (α-synuclein), Parkinson's disease (α-synuclein), multiple system atrophy (α-synuclein), Huntington's disease (polyglutamine), amyotrophic lateral sclerosis (TDP-43, FUS / TLS, RAN protein, SOD-1), spinocerebellar degeneration (polyglutamine, RAN protein), Creutzfeldt-Jakob disease (prion), and the like (note that examples of neurodegenerative disease causative proteins that are accumulated in each neurodegenerative disease are shown in parentheses). Among them, the therapeutic or preventive agent for neurodegenerative disease of the present invention is preferably a therapeutic or preventive agent for degenerative dementia. Examples of degenerative dementia include, but are not limited to, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, or dementia caused by amyotrophic lateral sclerosis. Among them, if frontotemporal dementia in which tau accumulates is further classified, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, etc. can be mentioned. The therapeutic or preventive effect of the agent for neurodegenerative disease of the present invention can be evaluated, for example, as shown in the examples described below, by administering the agent to a model animal that develops a neurodegenerative disease (e.g., degenerative dementia), and then subjecting it to a cognitive function test such as a Morris water maze test or a motor function test such as a rotarod test, or by staining and observing brain slices. [Dosage form, dosage and administration] The dosage form of the agent of the present invention is not particularly limited, but for example, a herbal medicine selected from the leaves, fruits, and seeds of Mamaki can be used as it is in any form such as crushed material, extract of crushed material, extraction residue of crushed material, etc., or can be formulated together with other ingredients such as desired excipients and / or carriers. In addition, when used in the form of a food (food of the present invention) or medicine (medicine of the present invention) containing the agent of the present invention, the leaves and / or fruits and / or seeds of Mamaki, which are the active ingredients of the agent of the present invention, can be mixed with other ingredients according to the form of the food or medicine, respectively, and used. Details will be described later. The method of use of the agent of the present invention is not particularly limited, but it is usually administered orally. In particular, the agent of the present invention is preferably used in the form of a food (the food of the present invention) or an oral medicine (the medicine of the present invention). Details will be described later. The dosage of the agent of the present invention is not particularly limited, but for example, the agent of the present invention can be administered to a subject so that the active ingredients, mamaki leaves and / or fruits and / or seeds, are usually 0.01 mg / day or more, or 0.1 mg / day or more, particularly 0.5 mg / day or more, or even 1.0 mg / day or more, and usually 10 g / day or less, particularly 5 g / day or less, or even 1 g / day or less. [Food] According to one aspect of the present invention, a food product containing the agent of the present invention (food product of the present invention) is provided. The food product of the present invention is characterized by containing any one of the agents of the present invention and is used for the intended purpose of the agent. The food of the present invention may be in any form that can be orally ingested, such as a solution, a suspension, an emulsion, a powder, a solid molding, etc. Also, in the same manner as the medicine of the present invention described below, it may be formed into a dosage form such as a capsule, a troche, a syrup, or a granule. The food of the present invention can be produced as, for example, beverages such as tea, black tea, coffee, soft drinks, alcoholic drinks, carbonated drinks, milk drinks, fruit juice drinks, nutritional drinks, concentrated drinks, powdered drinks (powdered juice, powdered soup, etc.); supplements; confectioneries such as candy, gummies, gums, chocolates, cookies, and biscuits; frozen desserts such as ice cream; dairy products such as yogurt and processed milk; flour products such as cereals, bread, and cake mix; noodles such as buckwheat; oil and fat processed products such as mayonnaise, whipped cream, and dressing; processed marine products; processed livestock products; and processed agricultural products.The food of the present invention can be produced by adding and containing the agent of the present invention during the production of these foods. In addition to other food ingredients, the food of the present invention can contain additives such as sweeteners, colorants, preservatives, thickeners, stabilizers, gelling agents or thickening agents, antioxidants such as ascorbic acid, color formers, bleaching agents, anti-mold or anti-fungal agents, yeast food, gum base, kansui, bittering agents, enzymes, gloss agents, flavorings, acidulants, chewing gum softeners, seasonings, tofu coagulants, emulsifiers, pH adjusters, leavening agents, nutritional enhancers such as vitamins, minerals and amino acids, and manufacturing agents, as necessary. The food of the present invention may be provided as a food that displays the action, effect, function, or use of the agent of the present invention under the system of each country. For example, in Japan, the food of the present invention may be produced as a food with health claims (specified health claims, functional food, nutritional functional food). The content of the leaves and / or fruits and / or seeds of mamaki, which are the active ingredients of the agent of the present invention, in the food of the present invention can be appropriately set within a range in which the effects of the present invention can be obtained, in the same manner as the agent of the present invention. Specifically, the content of the leaves and / or fruits and / or seeds of mamaki, which are the active ingredients of the agent of the present invention, can be adjusted so that the amount is usually 0.01 mg / day or more, or 0.1 mg / day or more, preferably 0.5 mg / day or more, or even 1.0 mg / day or more, and usually 10 g / day or less, preferably 5 g / day or less, or even 1 g / day or less. The number and frequency of ingestion of the food of the present invention is arbitrary and can be set appropriately as desired, such as once to several times a day, every day, every other day, every third day, or 1 to 7 days a week. By blending the leaves and / or fruits and / or seeds of mamaki in an amount necessary to obtain the effect of the agent of the present invention in accordance with the desired number and frequency of ingestion, the food of the present invention can be provided in which the desired effect can be expected depending on the type of desired action and effect. The food of the present invention is characterized by containing the agent of the present invention, and therefore shares the advantages of the various agents of the present invention and is extremely useful. In addition, since it is a food, it can be safely and easily used not only by patients suffering from a specific disease but also by healthy individuals. Furthermore, the food of the present invention can be used not only for humans, but also for animals other than humans to which the uses of the agent of the present invention can be applied. [Medicine] According to one aspect of the present invention, there is provided a medicament comprising the agent of the present invention (the medicament of the present invention). The medicament of the present invention is characterized by comprising any one of the agents of the present invention and is used for the intended use of the agent. The administration route of the pharmaceutical of the present invention is not limited, but it is usually an internal medicine (oral agent) that is administered orally. The pharmaceutical of the present invention can be manufactured by adding the agent of the present invention as an active ingredient, in any dosage form, such as capsules, including tablets, soft capsules, hard capsules, etc., solid preparations, including powders, granules, drops, pills, etc., semisolid preparations, including jellies, etc., and liquid preparations, including syrups, suspensions, and oral liquids, etc. In this case, the pharmaceutical of the present invention can be formulated as a pharmaceutical composition combining the agent of the present invention with other additives usually used in the manufacture of oral preparations, by a pharmaceutical manufacturing method known to those skilled in the art. Examples of additives used in the production of the medicament of the present invention include excipients, disintegrants, binders, lubricants, coating agents, dispersants, fluidizing agents, stabilizers, preservatives, buffers, flavoring agents, suspending agents, emulsifiers, fragrances, solubilizing agents, colorants, thickening agents, etc. Furthermore, by further combining with a pharma- ceutically acceptable carrier, it is possible to provide the medicament of the present invention with further enhanced action and effect of the agent of the present invention. The pharmaceutical of the present invention also includes products that are equivalent to pharmaceuticals under the systems of each country, such as quasi-drugs in Japan. The content of the leaves and / or fruits and / or seeds of mamaki, which are the active ingredients of the agent of the present invention, in the pharmaceutical composition of the present invention can be appropriately set within a range in which the effects of the present invention can be obtained, in the same manner as in the agent of the present invention. Specifically, the content of the leaves and / or fruits and / or seeds of mamaki, which are the active ingredients of the agent of the present invention, can be adjusted so that the amount is usually 0.01 mg / day or more, or 0.1 mg / day or more, preferably 0.5 mg / day or more, or even 1.0 mg / day or more, and usually 10 g / day or less, preferably 5 g / day or less, or even 1 g / day or less. The number and frequency of administration of the pharmaceutical of the present invention are arbitrary and can be set appropriately as desired, such as once to several times a day, every day, every other day, every third day, or 1 to 7 days a week. By blending the leaves and / or fruits and / or seeds of Mamaki in an amount necessary to obtain the effect of the agent of the present invention according to the desired number and frequency of administration, it is possible to provide an administration of the present invention that can be expected to have the desired effect according to the type of desired action effect. The pharmaceutical of the present invention is characterized by containing the agent of the present invention, and therefore shares the advantages of the agent and is extremely useful. Furthermore, the pharmaceutical agent of the present invention can be used not only in humans but also in animals other than humans to which the uses of the agent of the present invention can be applied. [method] According to one aspect of the present invention, there is provided a method for maintaining or improving brain function, a method for promoting the repair of nerve cells or inducing neurogenesis, a method for removing a neurodegenerative disease-causing protein that accumulates in the brain, or a method for treating or preventing a neurodegenerative disease (the method of the present invention), which comprises administering to a subject one or more of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki, the agent of the present invention, the food of the present invention, and the medicine of the present invention. In the method of the present invention, the leaves and / or fruits and / or seeds of Mamaki, which are the active ingredients of the agent of the present invention, may be administered to a subject in the form of the agent of the present invention, the food of the present invention, and / or the medicine of the present invention. The details are as described above in the explanation of the agent of the present invention, the food of the present invention, and the medicine of the present invention. The present invention will be described in more detail below with reference to examples. However, these examples are merely illustrative and are not intended to limit the present invention in any way. [Materials and Methods] Preparation of hot water extracts and non-extracted simple crushed powders of Mamaki leaves and fruits. Dried Mamaki tea leaves were purchased from Nakihalani Farm, LLC (Hawaii, USA). Hot water extract of Mamaki leaves was prepared at Technopro L&D (Tokyo, Japan). 250 g of Mamaki tea leaves were added to 3 L of water and steeped for 1 h. After boiling for 15 min with stirring, the mixture was left for 24 h. After removing the tea leaves, suction filtration was performed using a filter paper with a pore size of 8 μm. The filtrate was concentrated to 500 mL using an evaporator while heating at 40 °C. The concentrated solution was freeze-dried to obtain 66 g of extract powder. Non-extracted simple crushed powder of Mamaki leaves and fruits was prepared in our laboratory. Commercially available packages of Mamaki tea leaves contained a small amount of fruit (including seeds), so the tea leaves and fruit were manually separated and crushed into particles of 20-50 μm each using a grinder (Fine Powder Mill FM-100, Labonect, Sakai, Japan). These particles were collected and used as unextracted simple crushed powder. ・Mamaki ingredient analysis It is known that mamaki leaves contain catechin, chlorogenic acid, and rutin as major components (Non-Patent Document 10: Chun et al., Native Hawaiian medicines, First People's Productions Honolulu, (1994), pp. 216-217). The mamaki samples prepared above were sent to the Japan Food Research Laboratories (Tokyo, Japan) to measure the content of these polyphenols. For catechin, 0.4 g of material was suspended in 30 mL of a mixture of methanol and oxalic acid (8:2) and extracted by shaking for 10 min. After centrifugation, the supernatant was collected and the sediment was subjected to two more methanol extractions. The supernatants of the three extractions were combined to a total volume of 100 mL. The extract was diluted and separated by high performance liquid chromatography (HPLC) using a reversed-phase Inert Sustain C18 column (GL Sciences, Tokyo, Japan) with a 0.1% acetic acid and acetonitrile mixture (89:11) as the mobile phase. The eluted fractions were analyzed consecutively by electrospray ionization (ESI)-mass spectrometry (MS) using a XevoTQMS (Waters Corporation, Milford, MA). For chlorogenic acid, 0.2 g of material was suspended in 80 mL of a mixture of methanol and 0.02 M perchloric acid (1:9) and extracted by shaking for 10 min. After centrifugation, the supernatant was collected and the sediment was subjected to two more methanol extractions. The supernatants of the three extractions were combined to a total volume of 250 mL. The extract was separated by HPLC using a reversed-phase CAPCELL PAKC 18 ACR column (Osaka Soda, Osaka, Japan) with a mobile phase of water, acetonitrile, and phosphoric acid mixture (920:80:2). The absorbance of the eluted fractions at 325 nm was measured. Finally, for rutin, 0.4 g of material was suspended in 60 mL of a mixture of methanol and 2.5% acetic acid (8:2) and extracted by shaking for 10 min. After centrifugation, the supernatant was collected and the sediment was subjected to two further methanol extractions, and the supernatants of the three extractions were combined to a total volume of 200 mL. The extract was diluted and separated by HPLC using a reversed-phase Unison UK-C18 column (Imtakt USA, Portland, OR, USA) with a mobile phase of a mixture of water, acetonitrile, and 2-propanol (200:38:2) containing 0.4% citric acid. The absorbance of the eluted fractions was measured at 360 nm. ·mouse Four different neurodegenerative dementia mouse models were used. Tau784 mice are an FTD model that express both 3-repeat and 4-repeat human tau at adult age (with 4-repeat human tau being dominant) due to the presence of a tau intronic mutation (Umeda et al., Am. J. Pathol., (2013), 183[1]:211-25; and Umeda et al., Ann. Clin. Transl. Neurol., (2015), 2[3]:241-55). According to our previous studies, these mice show tau hyperphosphorylation, tau oligomerization, synaptic loss, and memory impairment at 6 months of age, microglial activation at 12 months of age, and neurofibrillary tangle formation and neuronal loss at 15 months of age due to the unbalanced expression of tau isoforms. APP23 mice are an AD model expressing human APP with the Swedish (KM670 / 671NL) mutation (Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. USA, (1997), 94:13287-92; Van Dam et al., Eur. J. Neurosci., (2003), 17[2]:388-96; and Umeda et al., Front. Neurosci., (2021), 15:763476). These mice show memory impairment at 3 months of age. According to previous studies by the present inventors, these mice show accumulation of Aβ oligomers, synaptic loss, and amyloid deposition at 15 months of age. Huα-Syn (A53T) line G2-3 mice were originally generated as a PD model expressing human α-synuclein with the A53T mutation (Non-Patent Document 30: Lee et al., Proc. Natl. Acad. Sci. USA, (2002), 99

[0013] :8968-73; and Non-Patent Document 31: Umeda et al., Int. J. Mol. Sci., (2021), 22:8453). According to the inventors' previous studies, these mice show accumulation of α-synuclein oligomers from 4 months of age, cognitive impairment at 6 months of age, and motor dysfunction at 9 months of age. Therefore, they can be considered a model of DLB ​​up to 9 months of age. C9-500 mice are a model of FTD / ALS introduced with the full-length human C9orf72 gene (Non-Patent Document 32: Liu et al., Neuron, (2016), 90[3]:521-534; and Non-Patent Document 33: Hatanaka et al., Biomedicines, (2022), 10[5]:1080). The mouse has a mutation in which the GGGGCC sequence in intron 1a is abnormally expanded to approximately 500 times (hexanucleotide repeat expansion, HRE), and has been reported to exhibit various pathologies including TDP-43 (Non-Patent Document 32). We confirmed that these mice showed accumulation of RNAG-quadruplex, dipeptide repeat proteins (DPRs) such as poly-GA and poly-GP, phosphorylated TDP-43, etc. that form RNA foci at 3 months of age, and showed synapse loss, neuron loss, and microglial activation at 6 months of age (Non-Patent Document 33 above). Incidentally, DPRs are produced by repeat-associated ATG-independent translation (RAN translation) controlled by double-stranded RNA-dependent protein kinase (PKR). The cognitive function of these mice began to decline at 4.5 months of age, but the motor function remained normal even at 12 months of age (Non-Patent Document 33 above). In other words, these mice can be considered a model of FTD-TDP up to 12 months of age. All transgenic (Tg) mice were maintained and used as heterozygous animals. All animal experiments were approved by the Ethics Committee of Osaka Municipal University (Osaka, Japan) and were performed in accordance with the Osaka Municipal University Animal Experimentation Guide. Treatment of mice To investigate the effect of hot water extract of Mamaki leaves, the extract powder was suspended in water at concentrations of 3.33, 0.33, and 0.10 mg / mL by sonication. 300 μL of each suspension (containing 1,000, 100, and 30 μg powder) was orally administered to male and female Tau784 mice, 5 days a week (Monday to Friday) for one month. As a control, the same volume of water was administered to age-matched Tg and non-Tg littermates. For APP23, Huα-Syn(A53T), and C9-500 mice, 0.33 mg / mL suspension (100 μg powder / 300 μL) was orally administered to male and female mice for one month. To compare the effects of three mamaki preparations, i.e., hot water extract of mamaki leaves, simple crushed powder of mamaki leaves, and simple crushed powder of mamaki fruits, each powder was suspended in water by sonication at a concentration of 0.10 mg / mL. 300 μL of each suspension (containing 30 μg powder) was orally administered to Tau784 mice for one month. To investigate the effects of polyphenols in Mamaki, catechin, chlorogenic acid, and rutin (all Fujifilm-Wako, Osaka, Japan) were placed in one tube and dissolved in water to prepare a mixture. The concentrations were adjusted to 0.29, 0.12, and 0.41 μg / mL, respectively. 300 μL of the mixture (containing 0.087 μg catechin, 0.036 μg chlorogenic acid, and 0.123 μg rutin) was orally administered to Tau784 mice for one month. The dose of these polyphenols corresponds to the amount contained in 30 μg of simply crushed fruit powder. A solution containing only catechin (0.087 μg / 300 μL) was also administered to Tau784 mice. Behavioral testing The spatial reference memory of mice was evaluated using the Morris water maze test (Non-Patent Document 34: Kelley Bromley-Brits et al., J. Vis. Exp., (2011), 53e2920). A 10 cm diameter platform was placed 1 cm below the water surface in one location of a circular pool with a diameter of 1 m so that it was not visible to the mouse. The mouse was placed in the pool and allowed to swim for 60 seconds, and the time it took to reach the platform was measured (represented as escape latency). If the mouse did not reach the platform within 60 seconds, the experimenter placed the mouse on the platform and allowed it to rest for a while. This trial was performed for each mouse five times a day at 5-minute intervals for four consecutive days. This measured memory acquisition ability. Histological analysis of neuropathology After the behavioral test, each group of mice was divided into two groups, one for histological analysis and the other for future biochemical analysis. Mice for histological analysis were perfused and fixed with 4% paraformaldehyde, and brain sections were prepared according to previous reports (Non-Patent Document 27: Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. USA, (1997), 94

[0024] :13287-92; and Non-Patent Document 33: Hatanaka et al., Biomedicines, (2022), 10[5]:1080), and neuropathology was stained by immunohistochemistry. The antibodies used in immunohistochemistry are shown below. Evaluation of pathology was performed by quantifying the staining intensity or staining area in a certain range of brain regions using NIH ImageJ software. Neuroinflammation (Non-Patent Document 35: Muzio et al., Front Neurosci., (2021), 24

[0015] :742065) was evaluated by counting the number of activated microglia that were Iba-1 positive in a certain area of ​​the brain. The correspondence between each neuropathology and the detection antibody is shown in the table below. Histological analysis of BDNF expression and neurogenesis BDNF expression was assessed in Tau784 mice treated with the three Mamaki preparations at 30 μg / day for one month. Brain sections were stained with anti-BDNF antibody (GTX132621; GeneTex, Irvine, CA), and staining intensity in a range of brain regions was quantified using NIH ImageJ software. Neurogenesis was evaluated using aged Huα-Syn (A53T) mice. Mice were orally administered a suspension of a simple crushed powder of mamaki fruit at 30 μg / day for one month. 5-Bromo-2'-deoxyuridine (BrdU; Sigma-Aldrich), a thymidine analogue that is selectively incorporated into the DNA of proliferating cells, was dissolved at 5 mg / mL in Tris-buffered saline, pH 7.6, and 300 μL of this solution (containing 1.5 mg) was intraperitoneally administered to mice daily for the last 5 days of mamaki administration. Brain sections were double-stained with anti-BrdU mouse monoclonal antibody (IBL) and anti-doublecortin rabbit polyclonal antibody (Abcam). Cells positive for both of these two antibodies were considered to be newly born neurons, and their numbers were counted in a certain range of brain regions. ・Statistical analysis Comparisons of means between three or more groups were performed using ANOVA or two-factor repeated measures ANOVA (for behavioral tests) followed by Fisher's PLSD test. Differences were considered significant when p-values ​​<0.05. [Example 1] Examination of the effect of hot water extract of Mamaki leaves (Leaf-ext) on Tau784 mice The effect of hot water extract of Mamaki leaves (Leaf-ext) on Tau784 mice was examined. 12-14 month old Tau784 mice (average body weight 31.8g) were orally administered 1000μg / day, 100μg / day, or 30μg / day of powdered hot water extract of Mamaki leaves (Leaf-ext) for one month. As controls, Tau784 mice and non-transgenic littermates of the same age were given the same amount of water. FIG. 1 is a graph showing the results of the Morris water maze test of Tau784 mice ("Tg+Leaf-ext" in the table) orally administered with a hot water extract of mamaki leaves (Leaf-ext) for one month, in comparison with Tau784 mice ("Tg" in the table) and non-transgenic mice ("Non-Tg" in the table) administered with water as a control. FIG. 1A is a graph showing the results of the groups administered with a dose of 1000 μg / day and 100 μg / day, and FIG. 1B is a graph showing the results of the group administered with a dose of 30 μg / day. As is clear from these results, administration of a hot water extract of mamaki leaves (Leaf-ext) improved the memory of Tau784 mice in a dose-dependent manner. In particular, in the groups administered with a dose of 1000 μg / day and 100 μg / day, the memory of Tau784 mice was improved to a level equivalent to that of non-transgenic littermates. FIG. 2 shows tau pathology in the entorhinal cortex of Tau784 mice ("Tau784+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Tau784 mice ("Tau784" in the table) administered water as a control. FIG. 2A shows photographs showing the staining results of phosphorylated tau and tau oligomers, and FIG. 2B shows a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of the hot water extract of Mamaki leaves (Leaf-ext) significantly reduced phosphorylated tau and tau oligomer levels in Tau784 mice. FIG. 3 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Tau784 mice ("Tau784+Leaf-ext" in the table) orally administered a dose of 100 μg / day of Mamaki leaf extract (Leaf-ext) for one month, in comparison with control Tau784 mice ("Tau784" in the table) and non-transgenic mice ("Non-Tg" in the table). FIG. 3A shows photographs showing the results of synaptophysin staining, and FIG. 3B shows a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of Mamaki leaf hot water extract (Leaf-ext) improved the synaptophysin level in the hippocampal CA2 / 3 region of Tau784 mice to a level equivalent to that of non-transgenic littermates. FIG. 4 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of Tau784 mice ("Tau784+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Tau784 mice ("Tau784" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as controls. FIG. 4A is a photograph showing the staining results of activated microglia, and FIG. 4B is a graph showing the number of positive cells in each photograph. As is clear from these results, administration of the hot water extract of mamaki leaves (Leaf-ext) improved the levels of activated microglia in the hippocampus (HC) and cerebral cortex (CTX) of Tau784 mice to levels equivalent to those of non-transgenic littermates. [Example 2] Examination of the effect of hot water extract of Mamaki leaves (Leaf-ext) on APP23 mice The effect of the hot water extract of Mamaki leaves (Leaf-ext) on APP23 mice was examined. 100 μg / day of powder of the hot water extract of Mamaki leaves (Leaf-ext) was orally administered to 14-17 month old APP23 mice (average body weight 30.1 g) for one month. As controls, the same amount of water was given to APP23 mice of the same age and non-transgenic littermates. 5 is a graph showing the results of a Morris water maze test of APP23 mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with APP23 mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. As is clear from these results, administration of the hot water extract of mamaki leaves (Leaf-ext) improved the memory of the APP23 mice to a level nearly equivalent to that of their non-genetically modified littermates (non-Tg). FIG. 6 shows amyloid pathology in the cerebral cortex and hippocampus of APP23 mice ("APP23+Leaf-ext" in the table) orally administered a dose of 100 μg / day of a hot water extract of mamaki leaves (Leaf-ext) for one month, compared with APP23 mice ("APP23" in the table) administered water as a control. FIG. 6A shows photographs showing the staining results of amyloid deposits and Aβ oligomers, and FIG. 6B shows a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of a hot water extract of mamaki leaves (Leaf-ext) significantly reduced the levels of amyloid deposits and Aβ oligomers in APP23 mice. FIG. 7 shows synaptophysin pathology in the hippocampal CA2 / 3 region of APP23 mice ("APP23+Leaf-ext" in the table) orally administered a dose of 100 μg / day of a hot water extract of mamaki leaves (Leaf-ext) for one month, in comparison with APP23 mice ("APP23" in the table) administered water as a control and non-genetically modified mice ("Non-Tg" in the table). FIG. 7A is a photograph showing the results of synaptophysin staining, and FIG. 7B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of a hot water extract of mamaki leaves (Leaf-ext) improved the synaptophysin level in the hippocampal CA2 / 3 region of APP23 mice to a level equivalent to that of non-genetically modified mice of the same litter. FIG. 8 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of APP23 mice ("APP23+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with APP23 mice ("APP23" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. FIG. 8A is a photograph showing the staining results of activated microglia, and FIG. 8B is a graph showing the number of positive cells in each photograph. As is clear from these results, the administration of hot water extract of mamaki leaves (Leaf-ext) improved the activated microglial levels in the hippocampus (HC) and cerebral cortex (CTX) of APP23 mice to levels equivalent to those of non-genetically modified mice of the same litter. [Example 3] Examination of the effect of hot water extract of Mamaki leaves (Leaf-ext) on Huα-Syn (A53T) mice The effect of hot water extract of Mamaki leaves (Leaf-ext) on Huα-Syn(A53T) mice was examined. 100 μg / day of hot water extract of Mamaki leaves (Leaf-ext) powder was orally administered to 7-8 month old Huα-Syn(A53T) mice (average body weight 28.4 g) for one month. As controls, Huα-Syn(A53T) mice of the same age and non-transgenic littermates were given the same amount of water. 9 is a graph showing the results of the Morris water maze test of Huα-Syn (A53T) mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with Huα-Syn (A53T) mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. As is clear from these results, the memory of the Huα-Syn (A53T) mice was improved to a level nearly equivalent to that of their non-genetically modified littermates (non-Tg) by administration of the hot water extract of mamaki leaves (Leaf-ext). Figures 10 and 11 show α-synuclein pathology in the hippocampus (HC) and entorhinal cortex (EC) of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) administered water as a control. Figure 10A is a photograph showing the staining results for phosphorylated α-synuclein, Figure 11A is a photograph showing the staining results for α-synuclein oligomers, and Figures 10B and 11B are graphs showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of the hot water extract of Mamaki leaves (Leaf-ext) significantly reduced the levels of phosphorylated α-synuclein and α-synuclein oligomers in Huα-Syn(A53T) mice. 12 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. FIG. 12A is a photograph showing the results of staining for synaptophysin, and FIG. 12B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of the hot water extract of Mamaki leaves (Leaf-ext) improved synaptophysin levels in the hippocampal CA2 / 3 region of Huα-Syn(A53T) mice to a level equivalent to that of non-transgenic littermates. FIG. 13 shows microglial pathology in the hippocampus (HC) and cerebral cortex (CTX) of Huα-Syn(A53T) mice ("αSyn-Tg+Leaf-ext" in the table) orally administered a hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as controls. FIG. 13A is a photograph showing the staining results of activated microglia, and FIG. 13B is a graph showing the number of positive cells in each photograph. As is clear from these results, administration of the hot water extract of Mamaki leaves (Leaf-ext) improved the levels of activated microglia in the hippocampus (HC) and cerebral cortex (CTX) of Huα-Syn(A53T) mice to levels equivalent to those of non-transgenic littermates. [Example 4] Examination of the effect of hot water extract of Mamaki leaves (Leaf-ext) on C9-500 mice The effect of hot water extract of Mamaki leaves (Leaf-ext) on C9-500 mice was examined. 9-10 month old C9-500 mice (average body weight 29.2 g) were orally administered 100 μg / day of hot water extract of Mamaki leaves (Leaf-ext) powder for one month. As a control, C9-500 mice of the same age and non-transgenic littermates were given the same amount of water. 14 is a graph showing the results of the Morris water maze test of C9-500 mice ("Tg+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, in comparison with C9-500 mice ("Tg" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. As is clear from these results, administration of the hot water extract of mamaki leaves (Leaf-ext) improved the memory of the C9-500 mice to a level nearly equivalent to that of their non-genetically modified littermates (non-Tg). 15 shows pathology caused by mutation of C9orf72 gene in the prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with C9-500 mice ("C9-500" in the table) administered water as a control. FIG. 15A shows photographs showing the staining results of RNA G-quadruplex, poly-GA, poly-GP, and phosphorylated TDP-43, and FIG. 15B shows graphs showing the quantification of the staining intensity of each photograph. These results clearly show that administration of the hot water extract of Mamaki leaves (Leaf-ext) significantly reduced the level of pathology caused by mutations in the C9orf72 gene in the prefrontal cortex (PFC) of C9-500 mice. FIG. 16 shows double-stranded RNA-dependent protein kinase (PKR) pathology in the prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a hot water extract of mamaki leaves (Leaf-ext) at a dose of 100 μg / day for one month, compared with C9-500 mice ("C9-500" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as a control. FIG. 16A is a photograph showing the staining results of phosphorylated PKR, and FIG. 16B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of hot water extract of mamaki leaves (Leaf-ext) reduced PKR levels in the prefrontal cortex (PFC) of C9-500 mice to a level equivalent to that of non-transgenic littermates. FIG. 17 shows synaptophysin pathology in the hippocampal CA2 / 3 region of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a dose of 100 μg / day of a hot water extract of mamaki leaves (Leaf-ext) for one month, compared with C9-500 mice ("C9-500" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. FIG. 17A is a photograph showing the results of synaptophysin staining, and FIG. 17B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, administration of a hot water extract of mamaki leaves (Leaf-ext) improved the synaptophysin level in the hippocampal CA2 / 3 region of C9-500 mice to a level equivalent to that of non-genetically modified mice of the same litter. FIG. 18 shows microglial pathology in the prefrontal cortex (PFC) of C9-500 mice ("C9-500+Leaf-ext" in the table) orally administered a dose of 100 μg / day of a hot water extract of mamaki leaves (Leaf-ext) for one month, compared with C9-500 mice ("C9-500" in the table) and non-genetically modified mice ("Non-Tg" in the table) administered water as a control. FIG. 18A is a photograph showing the staining results of activated microglia, and FIG. 18B is a graph showing the number of positive cells in each photograph. As is clear from these results, the administration of a hot water extract of mamaki leaves (Leaf-ext) improved the activated microglial levels in the prefrontal cortex (PFC) of C9-500 mice to a level close to that of non-genetically modified mice of the same litter. [Example 5] Examination of the effects of hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) on Tau784 mice The effects of hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) on Tau784 mice were examined. 7-9 month old Tau784 mice (average body weight 28.9 g) were orally administered 30 μg / day of hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) for one month. As controls, Tau784 mice and non-transgenic littermates of the same age were given the same amount of water. FIG. 19 is a graph showing the results of the Morris water maze test of Tau784 mice (each of which is "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of mamaki leaves (Leaf-ext), simple crushed powder of leaves (Leaf-pwd), and simple crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice ("Tg" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as a control. As is clear from these results, administration of hot water extract of mamaki leaves (Leaf-ext) improved the memory of Tau784 mice, but not to the extent of non-transgenic mice of the same litter. Administration of a powder of simply crushed Mamaki leaves (Leaf-pwd) improved the memory of Tau784 mice to the same level as that of non-transgenic littermates. Surprisingly, administration of a powder of simply crushed Mamaki fruits (including seeds) (Fruit-pwd) significantly enhanced the memory of Tau784 mice to a level even higher than that of non-transgenic littermates. FIG. 20 shows tau pathology in the entorhinal cortex of Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice (respectively "Tg+Leaf-pwd" in the table) administered water as a control. FIG. 20A is a photograph showing the staining results of phosphorylated tau and tau oligomers, and FIG. 20B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, the level of phosphorylated tau in the entorhinal cortex (EC) was significantly reduced by administration of the simple crushed powder of mamaki leaves (Leaf-pwd) and the simple crushed powder of fruit (including seeds) (Fruit-pwd), but the effect was stronger for the simple crushed powder of fruit (including seeds) (Fruit-pwd). On the other hand, the hot water extract of the leaves (Leaf-ext) showed only a slight effect. On the other hand, the level of tau oligomers was significantly reduced by both administrations, but the effect was highest for the simple crushed powder of fruit (including seeds) (Fruit-pwd) and weakest for the hot water extract of leaves (Leaf-ext). FIG. 21 shows synaptophysin pathology in the hippocampal CA2 / 3 region of Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice (respectively "Tau784" in the table) and non-transgenic mice (respectively "Non-Tg" in the table) administered water as a control. FIG. 21A is a photograph showing the results of staining for synaptophysin, and FIG. 21B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, synaptophysin levels in the hippocampal CA2 / 3 region of Tau784 mice were significantly restored by administration of the powder of simply crushed leaves (Leaf-pwd) and the powder of simply crushed fruits (including seeds) (Fruit-pwd), but the effect was stronger for the powder of simply crushed fruits (including seeds) (Fruit-pwd). On the other hand, the hot water extract of leaves (Leaf-ext) only incompletely restored the synaptophysin levels. FIG. 22 shows BDNF expression in the cerebral cortex (CTX) of Tau784 mice (respectively "Tg+Leaf-ext", "Tg+Leaf-pwd", and "Tg+Fruit-pwd" in the table) orally administered hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruits (including seeds) (Fruit-pwd) at a dose of 30 μg / day for one month, compared with Tau784 mice ("Tau784" in the table) and non-transgenic mice ("Non-Tg" in the table) administered water as a control. FIG. 22A is a photograph showing the staining results of BDNF, and FIG. 22B is a graph showing the results of quantifying the staining intensity of each photograph. As is clear from these results, the BDNF level in the cerebral cortex (CTX) of Tau784 mice was significantly increased by simply crushing powder of Mamaki fruit (including seeds) (Fruit-pwd) to a higher level than that of non-genetically modified mice littermates, and by simply crushing powder of leaves (Leaf-pwd) to a level equivalent to that of non-genetically modified mice littermates, whereas the hot water extract of leaves (Leaf-ext) showed only a slight effect. [Example 6] Examination of the effect of simple crushed powder of mamaki fruit (including seeds) (Fruit-pwd) on Huα-Syn (A53T) mice The effect of simple crushed powder of Mamaki fruit (including seeds) (Fruit-pwd) on Huα-Syn(A53T) mice was examined. Simple crushed powder of Mamaki fruit (including seeds) (Fruit-pwd) was orally administered at 30 μg / day for one month to 10-11 month old Huα-Syn(A53T) mice (average body weight 28.9 g). As a control, Huα-Syn(A53T) mice of the same age and non-transgenic littermates were given the same amount of water. FIG. 23 shows the neurogenesis levels in the dentate gyrus (DG) and substantia nigra (SN) of Huα-Syn(A53T) mice ("αSyn-Tg+Fruit-pwd") orally administered a simple crushed powder (including seeds) of mamaki fruit at a dose of 30 μg / day for one month, compared with Huα-Syn(A53T) mice ("αSyn-Tg" in the table) and non-transgenic mice ("Non-Tg" in the table) administered with water as a control. FIG. 23A shows immunofluorescent staining photographs of BrdU (red) and doublecortin (DCX) (green). Double-positive cells (yellow) that are both positive for BrdU (red) and DCX (green) were considered to be newborn neurons. FIG. 23B shows a graph showing the results of quantifying the number of double-positive cells (yellow) in each photograph. As is clear from these results, administration of a simple crushed powder of Mamaki fruit (including seeds) (Fruit-pwd) surprisingly improved the neurogenesis levels in the dentate gyrus (DG) and substantia nigra (SN) of Huα-Syn(A53T) mice to a level far exceeding that of non-transgenic littermates. These results suggest that Mamaki fruit (including seeds) has the effect of promoting brain rejuvenation through neuronal repair and regeneration. [Example 7] Examination of the effects of three types of polyphenols on Tau784 mice It has been reported that the three polyphenols contained in Mamaki, namely, catechin, chlorogenic acid, and rutin, all have anti-dementia effects. Therefore, the above-mentioned various effects contained in the hot water extract of Mamaki leaves (Leaf-ext), the simple crushed powder of the leaves (Leaf-pwd), and the simple crushed powder of the fruit (including seeds) (Fruit-pwd) may be due to these polyphenols. Therefore, the effects of the three polyphenols, namely, catechin, chlorogenic acid, and rutin, on Tau784 mice were examined. First, the contents of the three polyphenols, i.e., catechin, chlorogenic acid, and rutin, contained in 100 g of each of the hot water extract of Mamaki leaves (Leaf-ext), the powder of simply crushed leaves (Leaf-pwd), and the powder of simply crushed fruits (including seeds) (Fruit-pwd) were quantified. The results are shown in the table below. Next, 8-10 month old Tau784 mice (average body weight 32.0 g) were orally administered a mixture of 0.087 μg catechin, 0.036 μg chlorogenic acid, and 0.123 μg rutin, or 0.087 μg catechin alone for one month. The doses of these polyphenols were equivalent to the amounts contained in 30 μg of simply crushed powder of mamaki fruit (including seeds). As controls, Huα-Syn(A53T) mice and non-transgenic littermates of the same age were given the same amount of water. FIG. 24 is a graph showing the results of the Morris water maze test of Tau784 mice orally administered a mixture of 0.087 μg catechin, 0.036 μg chlorogenic acid, and 0.123 μg rutin ("Tg+3 polyphenol mixture" in the table) or 0.087 μg catechin alone ("Tg+chatechin" in the table) for one month, compared with Tau784 mice administered water as a control ("Tg" in the table) and non-transgenic mice ("Non-Tg" in the table). As is clear from these results, administration of the mixture of three polyphenols improved the memory of Tau784 mice, but the effect was far inferior to that of non-transgenic littermates and was incomplete. Furthermore, administration of catechin alone showed only a weaker effect than the polyphenol mixture. Comparing these results with the effects of each of the above-mentioned Examples 1 to 6, it can be seen that the various effects of the hot water extract of Mamaki leaves (Leaf-ext), simply crushed powder of leaves (Leaf-pwd), and simply crushed powder of fruit (including seeds) (Fruit-pwd) are not solely due to the three types of polyphenols mentioned above, but rather are largely due to the contribution of other unknown components contained in Mamaki. The present invention can be widely applied to fields such as functional foods and medicines where maintenance or improvement of cognitive function is required, and its utility is extremely valuable.

Claims

1. An agent for maintaining or improving brain function, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki.

2. The agent for maintaining or improving brain function according to claim 1 , wherein the brain function is a cognitive function.

3. An agent for promoting the repair of nerve cells or inducing neurogenesis, comprising a medicinal herb selected from the leaves, fruits, and seeds of Mamaki.

4. An agent for removing proteins that cause neurodegenerative diseases and accumulate in the brain, comprising a herbal medicine selected from the leaves, fruits, and seeds of Mamaki.

5. 5. The agent according to claim 4, wherein the neurodegenerative disease-causing protein is one or more proteins selected from amyloid beta (Aβ), tau, α-synuclein, TDP-43, FUS / TLS, polyglutamine, a protein derived from RAN (repeat-associated non-ATG) translation, prion, and SOD-1.

6. A therapeutic or preventive agent for neurodegenerative diseases, comprising a medicinal herb selected from the leaves, fruits, and seeds of Mamaki.

7. The agent according to claim 6, wherein the neurodegenerative disease is degenerative dementia.

8. The agent according to claim 7, wherein the degenerative dementia is one or more types of dementia selected from Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and dementia caused by Parkinson's disease or amyotrophic lateral sclerosis.

9. The agent according to claim 1, wherein the herbal medicine selected from the leaves, fruits, and seeds of Mamaki is crushed and / or extract of Mamaki leaves and / or fruits and / or seeds.

10. The agent according to claim 1, wherein the herbal medicine is administered to a subject in an amount of 0.01 mg to 10 g per day.

11. The agent according to any one of claims 1 to 10, (1) Maintenance or improvement of brain function, (2) promoting repair of nerve cells or inducing neurogenesis; (3) Removal of neurodegenerative disease-causing proteins that accumulate in the brain, and / or (4) Treatment or prevention of neurodegenerative diseases Food for.

12. The agent according to any one of claims 1 to 10, (1) Maintenance or improvement of brain function, (2) promoting repair of nerve cells or inducing neurogenesis; (3) Removal of neurodegenerative disease-causing proteins that accumulate in the brain, and / or (4) Treatment or prevention of neurodegenerative diseases Medicine for.

13. 1. Use of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki in the manufacture of a food or medicine for maintaining or improving brain function in a subject.

14. 14. The use according to claim 13, wherein the brain function is a cognitive function.

15. 1. Use of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki in the manufacture of a food or medicine for promoting the repair of nerve cells or inducing neurogenesis in a subject.

16. 1. Use of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki in the manufacture of a food or medicine for removing a neurodegenerative disease-causing protein that accumulates in the brain of a subject.

17. The use according to claim 16, wherein the neurodegenerative disease-causing protein is one or more proteins selected from amyloid beta (Aβ), tau, α-synuclein, TDP-43, FUS / TLS, polyglutamine, a protein derived from repeat-associated non-ATG (RAN) translation, prion, and SOD-1.

18. 1. Use of a herbal medicine selected from the leaves, fruits, and seeds of Mamaki in the manufacture of a food or medicine for treating or preventing a neurodegenerative disease in a subject.

19. 19. The use according to claim 18, wherein the neurodegenerative disease is degenerative dementia.

20. 20. The use according to claim 19, wherein the degenerative dementia is one or more types of dementia selected from Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and dementia caused by Parkinson's disease or amyotrophic lateral sclerosis.

21. The use according to any one of claims 13 to 20, wherein the herbal medicine selected from the leaves, fruits, and seeds of Mamaki is crushed material and / or extract of Mamaki leaves and / or fruits and / or seeds.

22. The use according to any one of claims 13 to 220, wherein the herbal medicine is administered to a subject in an amount of 0.01 mg to 10 g per day.