Application of transaldolase TALDO1 in preparation of medicine for preventing and / or treating Alzheimer disease

Abstract

The invention discloses an application of transaldolase TALDO1 in preparation of a medicine for preventing and / or treating Alzheimer's disease, and proposes that TALDO1 is a medicine target of Alzheimer's disease (AD), and the TALDO1 is obviously reduced in the temporal lobe cortex of an AD patient and neurons and synaptic components of a disease model mouse. By improving the expression level of the TALDO1 in hippocampus and cortical neurons, the incubation period of an AD model mouse for finding a platform in a water maze can be shortened, the residence time and path in a target quadrant can be prolonged, the neuron density and the number of dendritic spines in the brain of the AD model mouse can be increased, amyloid plaques are reduced, the AD pathology is improved, and the AD model mouse can be used for preparing a medicine for treating the diseases. It is indicated that by improving the expression level of the neuron TALDO1, AD model mouse learning and memory disorders can be improved, amyloid plaque pathology and neuron degeneration are delayed and controlled, and it is proved that the TALDO1 can be used as a target of drugs for preventing and / or treating AD.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to the use of transaldolase TALDO1 in the preparation of drugs for preventing and / or treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease with clinical manifestations of cognitive memory dysfunction, mental and behavioral abnormalities, and deterioration of daily living ability. It is also one of the main causes of dementia in the elderly worldwide. With the substantial increase in the life expectancy of the global population, the occurrence of AD has imposed a heavy economic and social burden on human society and has become the fifth leading cause of death among people over 65 years old worldwide. Multiple pathological factors in AD, such as Aβ, Tau protein, and glial cells, can lead to neuronal and synaptic dysfunction, but the complex mechanism of neuronal degeneration in AD has not yet been fully elucidated. At present, there is an urgent need for in-depth research on the pathophysiological changes in neurons and synapses in AD, which will help develop disease-modifying therapies that can delay or prevent neuronal functional damage.

[0003] Neurons tend to use glucose to enter glycolysis through the pentose phosphate pathway to participate in energy supply and maintain function. Inhibition of the pentose phosphate pathway can lead to energy supply disorders and insufficient supply of reduced nicotinamide adenine dinucleotide phosphate (NADPH), impaired antioxidant effects, and affect various biosynthetic processes. In addition, the flux of the pentose phosphate pathway and aerobic oxidation is significantly reduced in AD model mice, resulting in a decrease in antioxidant reserves and energy supply in the brain, which may be an important cause of impaired neuronal activity and function in AD.

[0004] Transaldolase 1 (TALDO1) is the second rate-limiting enzyme in the non-oxidative phase of the pentose phosphate pathway. It catalyzes the reversible transfer of a three-carbon unit (dihydroxyacetone) between various sugar phosphates, closely links the pentose phosphate pathway and the glycolysis pathway, and plays an important role in maintaining mitochondrial function, reducing the production of peroxides, maintaining DNA stability and metabolic balance. Clinical studies have shown that patients with TALDO1 deficiency experience mild cognitive impairment or motor delay, further highlighting the importance and potential clinical significance of TALDO1 in the brain. The Alzdata database observed a downregulation trend of TALDO1 in the hippocampus and cortex of AD patients, but there has been no literature report on the role of TALDO1 in the pathophysiological mechanism of AD. At the same time, a search of domestic and foreign literature on existing technologies has not yet found any research reports on the relationship between TALDO1 and AD treatment. Summary of the invention

[0005] The main purpose of the present invention is to provide the use of TALDO1 in the preparation of drugs for preventing and / or treating AD, and the TALDO1 gene or its encoded protein is used as a target of the drug for preventing and / or treating AD.

[0006] To achieve the above object, the technical solution adopted by the present invention is:

[0007] In a first aspect, the present invention provides use of a TALDO1 upregulator in the preparation of a medicament for preventing and / or treating AD.

[0008] Preferably, the TALDO1 up-regulator includes a substance capable of increasing the expression level of TALDO1, and / or a substance capable of increasing the activity and stability of TALDO1, and / or a substance capable of increasing the effective action time of TALDO1.

[0009] Preferably, the TALDO1 up-regulator includes an RNA fragment complementary to the cDNA base sequence of TALDO1, or a nucleotide sequence, polypeptide, protein that increases the expression of TALDO1, or a compound that increases the functional activity of TALDO1.

[0010] More preferably, the TALDO1 upregulator is a retrovirus that expresses an RNA fragment complementary to the cDNA base sequence of TALDO1.

[0011] In a second aspect, the present invention provides the use of the TALDO1 gene or its encoded protein as a target in the preparation of a drug for preventing and / or treating AD.

[0012] Preferably, the drug has at least any one of the following functions:

[0013] a) promoting the activity and / or content of TALDO1;

[0014] b) Reduce AD ​​neuronal damage and synaptic disorders;

[0015] c) Improve cognitive impairment in AD model mice and / or AD patients and delay the pathological progression of AD.

[0016] Preferably, the drug comprises an effective amount of a neuron-specifically expressed TALDO1 upregulator, and a pharmaceutically acceptable carrier or excipient.

[0017] More preferably, the TALDO1 upregulator is used alone or in combination with a commercially available drug for preventing and / or treating AD.

[0018] Preferably, the dosage form of the drug is selected from at least one of an injection preparation, an oral preparation, nasal drops, a spray preparation, an ointment preparation or a patch.

[0019] In a third aspect, the present invention provides the use of the TALDO1 gene or its encoded protein as a target in preparing a drug screening model for preventing and / or treating AD.

[0020] Compared with the prior art, the beneficial effect of the present invention is that the present invention proposes for the first time that TALDO1 is a drug target for AD. Experiments have shown that TALDO1 is downregulated in crude extracts of synaptosomes of brain neurons of clinical AD patients and AD model mice. Restoring TALDO1 in brain neurons of AD model mice improves energy metabolism in the brain, can reverse neuronal damage, increase dendritic spine density, and further reduce excessive deposition of amyloid plaques, alleviating cognitive impairment in AD model mice. These results indicate that TALDO1 is an important therapeutic target for AD, and are of great significance for the development, prevention and treatment of drugs for this type of disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : TALDO1 levels in temporal cortex samples of AD patients and non-dementia control group in the embodiment; wherein A is the protein blot of TALDO1 in crude synaptosome extracts of temporal cortex neurons of AD patients and non-dementia control group; B is the statistical graph of TALDO1 protein expression in A (***P<0.001 versus non-dementia control group. n(non-dementia control)=12, n(AD patients)=16, Data are shown as mean±SEM).

[0022] Figure 2 The TALDO1 protein levels in the synaptosome components of cortical neurons of 5×FAD mice in the example; wherein: A is a protein blot of TALDO1 in crude extracts of synaptosomes of cortical neurons of 2.5-month-old 5×FAD and control wild-type mice; B is a statistical graph of the expression level of TALDO1 protein in A (**P<0.01 versus wild-type mice. n=4, Data are shown as mean±SEM).

[0023] Figure 3 The TALDO1 expression levels in the hippocampus and cortex of 5×FAD mice in the example; wherein: A is the immunofluorescence image of TALDO1 in the hippocampus and cortex of 5×FAD and wild-type mice; B is the fluorescence quantitative statistical graph of TALDO1 in Figure A (*P<0.05, **P<0.01 versus wild-type mice. n=4, Data are shown as mean±SEM).

[0024] Figure 4The effects of the lentivirus (LV-hSyn-TALDO1-3Flag-2A-EGFP, hereinafter referred to as TALDO1 overexpression lentivirus) containing a neuron-specific promoter expressing an RNA fragment complementary to the cDNA base sequence of TALDO1 in the example on the expression of TALDO1 protein in the brain of 5×FAD mice; wherein: A is a protein blotting image of TALDO1 in the hippocampus of 5×FAD and wild-type mice 45 days after intracerebroventricular injection of TALDO1 overexpression lentivirus or control virus; B is a protein blotting image of TALDO1 in the cortex of 5×FAD and wild-type mice 45 days after injection of TALDO1 overexpression lentivirus or control virus.

[0025] Figure 5 The learning and memory abilities of 5×FAD mice in the embodiment 50 days after stereotaxic injection of TALDO1 overexpression lentivirus and control lentivirus via the lateral ventricle; wherein: A is the latency time of the overexpression group and the control group mice to find the target quadrant, B is the swimming speed of the overexpression group and the control group mice, C is the percentage of the time the overexpression group and the control group mice stayed in the target quadrant, D is the percentage of the distance the overexpression group and the control group mice stayed in the target quadrant, and E is the motion trajectory diagram of the overexpression group and the control group mice (*P<0.05, **P<0.01 versus 5×FAD injected with TALDO1 overexpression virus group, n=8-10, Data are shown as mean±SEM).

[0026] Figure 6 The figures are the neuronal structure and dendritic spine density of the hippocampus of mice in the 5×FAD overexpression group and the control group in the embodiment; wherein: A is the Golgi staining image of the hippocampus of mice injected with TALDO1 overexpression lentivirus or control lentivirus; B is a statistical graph of the neuronal staining intensity in Figure A; C is a statistical graph of the number of dendritic spines in Figure A (*P<0.05, **P<0.01 versus 5×FAD injected with TALDO1 overexpression virus group, n=6, Data are shown as mean±SEM).

[0027] Figure 7 The amyloid protein pathology of 5×FAD mice two months after intracerebroventricular injection of TALDO1 overexpression lentivirus or control lentivirus in the example; wherein: A is an immunofluorescence image of amyloid plaques in the hippocampus and cortex of 5×FAD mice injected with TALDO1 overexpression lentivirus or control lentivirus; B is a statistical graph of amyloid plaques in Figure A (**P<0.01versus5×FAD injection control virus group, n=6, Data are shown as mean±SEM). DETAILED DESCRIPTION

[0028] In order to more fully understand and demonstrate the technical solutions, purposes and advantages of the present invention, the technical effects produced by the present invention are further described in detail and completely in conjunction with the accompanying drawings and specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all. It should be pointed out that for ordinary technicians in this field, other embodiments obtained without departing from the concept of the present invention all belong to the protection scope of the present invention.

[0029] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0030] The inventors of the present invention have found that TALDO1 expression is significantly reduced in brain tissues of AD patients and model mice, and is involved in the structure of neurons and synaptic function in the brain, as well as the generation of amyloid pathology. Administration of TALDO1 overexpression lentivirus into the brains of AD model mice can improve and restore degenerative changes in neurons and synapses in the brain, significantly alleviate the occurrence of amyloid pathology in the brain, and improve the learning and memory ability of mice, indicating that TALDO1 has clinical application prospects for the treatment of AD, thereby completing the present invention.

[0031] The present invention proposes the use of a TALDO1 upregulator in the preparation of a drug for preventing and / or treating AD.

[0032] The term "preventing a disease" refers, for example, to preventing the development of clinical symptoms of a disease in a mammal that may have been exposed or predisposed to the disease but has not yet experienced or displayed symptoms of the disease.

[0033] The term "treating a disease" may refer to inhibiting the disease, such as arresting or reducing the development of the disease or its clinical symptoms, or alleviating the disease, such as causing regression of the disease or its clinical symptoms.

[0034] TALDO1 upregulators include substances that can increase the level of TALDO1, such as RNA fragments that are complementary to the cDNA base sequence of TALDO1. In addition, it should be understood that TALDO1 upregulators also include substances that can increase the activity and stability of TALDO1, and substances that can increase the effective action time of TALDO1. For example, TALDO1 upregulators also include nucleotide sequences, polypeptides, proteins that can increase the expression of TALDO1, or compounds that increase the functional activity of TALDO1. TALDO1 upregulators improve the function of neurons and synapses in the AD brain and reduce the effects of amyloid pathology. The application of TALDO1 upregulators can effectively inhibit the progression of pathological phenotypes in AD model mice and improve learning and memory abilities.

[0035] The study found that TALDO1 was significantly reduced in the neurons and synaptosome components of brain tissue of AD patients and 5×FAD mice.

[0036] For AD model mice, intracerebroventricular injection of TALDO1 overexpression lentivirus can alleviate brain energy metabolism and reduce neuronal oxidative stress, thereby improving neuronal structure and synaptic function. The homeostatic recovery of over-excited neurons under stress conditions can reduce Aβ propagation, thereby reducing the production of amyloid protein pathology and promoting improvements in learning and memory abilities.

[0037] The drug for preventing and / or treating AD in the present invention can be a viral vector gene therapy drug for preparing AD. TALDO1 can be used as a target for developing, screening or preparing drugs for preventing and / or treating AD. TALDO1 is used as an object of action to screen candidate substances, and substances that can increase TALDO1 expression, increase TALDO1 activity and stability, and / or reduce the effective action time of TALDO1 are screened as alternative drugs for preventing and / or treating AD.

[0038] In some embodiments, a drug screening model targeting TALDO1 is established to screen drugs that target TALDO1. A system expressing TALDO1 is treated with a candidate substance, and the expression of TALDO1 in the system is detected. If the expression or activity of TALDO1 is increased, it indicates that the candidate substance is a potential substance for preventing and / or treating AD.

[0039] The present invention provides a drug, namely an effective amount of a neuron-specifically expressed TALDO1 upregulator, and a pharmaceutically acceptable carrier or excipient.

[0040] By "effective amount" is meant an amount of a TALDO1 upregulator that (i) treats a particular disease, condition or disorder; (ii) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0041] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients without significantly reducing the efficacy of the active ingredients. Pharmaceutically acceptable carriers or excipients include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0042] In some embodiments, the TALDO1 up-regulator can be prepared into an injection preparation, an oral preparation, a nasal drop, a spray preparation, an ointment preparation or a patch according to common methods for preparing drugs.

[0043] In some embodiments, TALDO1 upregulators can also be used in combination with other drugs for preventing and / or treating AD.

[0044] The following examples further explain and illustrate the present invention.

[0045] Example 1: TALDO1 levels are significantly reduced in synaptosomes of AD patients and AD model mice

[0046] A total of 28 human brain tissue samples were used with the approval of the Ethics Review Committee of Shanghai Jiao Tong University School of Medicine. All temporal cortex samples of AD patients and non-dementia controls were provided by the Netherlands Brain Bank. Among them, 16 were AD patients and 12 were non-dementia controls of the same age.

[0047] Four 2.5-month-old 5×FAD transgenic mice and four wild-type control mice of the same age and background were selected. After anesthesia, the brains were removed by perfusion and the brain tissues were divided into two halves. One half was used for the preparation of crude neuronal synaptosome extract samples, and the other half was fixed with paraformaldehyde and paraffin sections were made for immunofluorescence experiments. The relevant operations were in accordance with ethical operation standards and procedures.

[0048] Extraction of crude neuronal synaptic extracts: Weigh an appropriate amount of human temporal cortex or mouse hippocampal cortex tissue, add 100 μL of homogenate solution (containing 50 mM NaF, 1 mM Na 3 VO 4 , 2mM EDTA, 1× protease inhibitor and 0.1mg / mL benzamidine in 0.32M sucrose HEPES buffer, pH 7.4), use a grinder equipped with a grinding rod to slowly move up and down at a speed of 80 rpm for 10 times to grind the tissue, and let it stand on ice for 5 minutes to obtain a whole tissue homogenate. Centrifuge the whole tissue homogenate at 4°C and 1000g for 10 minutes to obtain a supernatant and a precipitate P1; take the supernatant, centrifuge at 4°C and 10000g for 15 minutes, and retain the precipitate; mix the precipitates obtained from the two centrifugations and resuspend them with 10 times the volume of 0.32M sucrose HEPES buffer, centrifuge at 4°C and 10000g for 15 minutes, and the resulting precipitate is the crude extract of neuronal synapses.

[0049] Western blotting experiment: The protein samples were prepared and the protein concentration was quantified using a BCA kit. After protein denaturation, the samples were separated by SDS-PAGE electrophoresis and transferred to a methanol-activated PVDF membrane. The membrane was blocked with 5% skim milk powder (diluted with TBS) at room temperature for 2 h, and the membrane was washed once with TBST for 5 min. The target protein TALDO1 antibody (purchased from KleanAB, product number P101222, diluted 1:1000) and the internal reference protein β-actin antibody (purchased from Cell Signaling Technology, product number 66009-1-Ig, diluted 1:10000) were incubated on a shaker at 4°C overnight, and the TBST was washed three times for 15 min each time. The HRP-labeled secondary antibody (purchased from Cell Signaling Technology, product number #7074 and #7076, diluted 1:3000) was incubated at room temperature for 1 h, and the membrane was washed three times with TBST for 15 min each time. The membrane was exposed with ECL luminescent solution, developed, and grayscale analysis was performed using Image J software.

[0050] Preparation of paraffin sections of brain tissue: Anesthetize mice with isoflurane, and remove the brain after perfusing the heart. After fully fixing the brain tissue in 4% paraformaldehyde fixative, place it in an embedding box and immerse it in a gradient ethanol solution for dehydration. Immerse the tissue in a xylene solution for 15 minutes and repeat once. Then place the tissue in paraffin and treat it at 60°C for 1h; repeat the same steps again. Avoid creating bubbles when embedding the tissue in paraffin to ensure sample quality. Cut the tissue block into slices with a thickness of 8μm, unfold it in water at 42°C, pick it up vertically with a fine brush, and place the slices in an oven at 65°C to dry for 1h. After completion, the slices can be saved.

[0051] Immunofluorescence staining: Paraffin sections with clear cortical and hippocampal structures were selected and placed in a 60°C oven for 30 minutes. Dewax and rehydrate by soaking in the following steps: dewax twice in xylene solution, 10 minutes each time; soak twice in anhydrous ethanol, 95% ethanol, and 75% ethanol, 5 minutes each time; soak once in distilled water, 5 minutes. Antigen repair treatment was performed on the sections using Tris-EDTA (pH 9.0) antigen repair solution at 100°C for 30 minutes. Then it was cooled naturally to room temperature. The repair solution remaining on the brain slices was washed 3 times with PBS, 5 minutes each time. After completing the steps of brain slice blocking, primary antibody incubation (anti-TALDO1 dilution ratio 1:200, DAPI dilution ratio 1:1000), PBST washing, secondary antibody incubation, and nuclear staining, the sections were sealed with anti-fluorescence quenching sealing solution. Images were acquired and saved using a Leica SP8 confocal microscope.

[0052] In Example 1, Western blotting and immunofluorescence experiments showed that Figure 1As shown in Figure 2, TALDO1 levels were significantly reduced in the synaptosome fraction of neurons in the temporal cortex of AD patients. Figure 2 and 3 As shown, TALDO1 levels were significantly reduced in the synaptosomal components of neurons and in the cortex and hippocampus regions of brain slices of AD model mice.

[0053] Example 2: Improving the expression of TALDO1 in neurons improves cognitive dysfunction in 5×FAD mice

[0054] AD model mice were injected with TALDO1 overexpression lentivirus via lateral ventricle injection at 5×FAD, i.e., a lentivirus containing a neuron-specific promoter and an RNA fragment complementary to the cDNA base sequence of TALDO1 (LV-hSyn-TALDO1-3Flag-2A-EGFP). This lentivirus can stably increase the expression of TALDO1 in the mouse brain for a long time, and the virus titer is 1×10 9 TU / mL, the injection volume was 3 μL; the control group was injected with the control virus LV-hSyn-3Flag-2A-EGFP (the virus titer was 1×10 9 TU / mL).

[0055] This experiment was approved by the Animal Experiment Ethics Committee of Shanghai Jiao Tong University School of Medicine and was performed in accordance with the Animal Experimentation Guide.

[0056] 2.5-month-old male 5×FAD and wild-type mice were randomly divided into wild-type mice injected with control virus group, wild-type mice injected with TALDO1 overexpression virus group, 5×FAD mice injected with control virus group and 5×FAD mice injected with TALDO1 overexpression virus group, with 8-10 mice in each group. The mice were anesthetized with isoflurane. After the mice had no corneal reaction, the hair on the top of the head was shaved and the scalp was disinfected with iodine tincture. The skull of the mouse was fixed with left and right ear bars and adjusted to the appropriate height. The scalp was quickly cut along the midline of the skull with a sharp surgical blade. A small amount of hydrogen peroxide was used to wipe the mouse dura mater to expose the cross-shaped anterior fontanelle and the herringbone posterior fontanelle. According to the small animal brain stereotaxic atlas, the intersection of the anterior fontanelle was used as the starting point, and the bilateral lateral ventricles were marked (0.3mm behind the anterior fontanelle, 1.0mm to the left and right of the midline, and 2.0mm in depth), and the skull was gently polished with a drill to open the skull. A Hamilton needle and microinjector were used to slowly and vertically insert the needle into the lateral ventricle until the injection site, and then the needle was stopped for 2 min. 3 μL of lentivirus (titer 1×10 9 TU / mL), injection time 5min, stop time 5min, slowly pull out the needle after injection, seal the wound with tissue glue and apply erythromycin ointment for disinfection, and place the mice in a 37℃ incubator to wait for awakening. After 50 days, the Morris water maze was used to test the learning and memory ability of mice. After behavioral studies, the mice were killed and the brains were taken out, fixed and sliced ​​for subsequent staining.

[0057] Western blot and Morris water maze experiments showed that Figure 4 As shown in the figure, TALDO1 overexpression lentivirus can significantly increase the expression of TALDO1 protein in the hippocampus and cortex of 5×FAD mice. Figure 5 As shown in the figure, the behavioral experiment results show that the injection of TALDO1 overexpression virus can significantly shorten the latency of 5×FAD mice to reach the platform and increase the residence time and distance in the target quadrant. From the movement trajectory diagram of the control group mice, it can be seen that compared with the control group 5×FAD mice, the learning and memory ability of 5×FAD mice injected with TALDO1 overexpression virus is significantly improved.

[0058] Example 3: Improving TALDO1 expression in neurons improves neuronal damage and amyloid deposition in the brain of 5×FAD mice

[0059] Golgi staining: 24 hours before taking the mouse brain, mix equal amounts of A and B solutions in the Golgi staining kit, immerse the brain tissue in a liquid mixed with equal volumes of solution A and B, replace the new immersion solution the next day, and store it at room temperature in the dark. Two weeks later, discard the A and B mixture, transfer the brain tissue to solution C, and immerse it at room temperature in the dark for 72 hours. Replace solution C once after 24 hours, embed the brain tissue with OCT, add solution C on a gelatin-coated slide, and use a freezing microtome to cut brain slices with clear hippocampal structure from the coronal plane. The slice thickness is 100 μm, and the slices are naturally air-dried at room temperature in the dark. The brain slices were rinsed twice with double distilled water for 4 minutes each time, and the slices were soaked in a solution mixed with 1 part of solution D, 1 part of solution E and 2 parts of double distilled water for 10 minutes. The brain slices were rinsed twice with double distilled water for 4 minutes each time, and the brain slices were dehydrated in 50%, 75% and 95% ethanol in a gradient manner, with each concentration gradient dehydration for 4 minutes. The slices were dehydrated in anhydrous ethanol for 4 times, each time for 4 minutes, and the slides were placed in xylene for transparent treatment, repeated 3 times, each time for 4 minutes, and sealed with resin sealing agent, and dried in the dark. The neurons and single dendritic spines in the hippocampus were photographed under an upright camera microscope and the data were saved.

[0060] Paraffin brain sections were stained for amyloid protein. Aβ antibody was purchased from Cell Signaling Technology, catalog number 2450T, with a dilution ratio of 1:200. Images were acquired and stored using a Leica SP8 confocal microscope.

[0061] like Figure 6As shown, the Golgi staining results showed that the number of hippocampal neurons in 5×FAD mice was significantly reduced and the density of dendritic spines decreased. The density of neurons and the number of dendritic spines in the hippocampus of 5×FAD mice injected with TALDO1 overexpression lentivirus increased, indicating that increasing the expression level of neuronal TALDO1 can reduce neuronal and synaptic function damage in 5×FAD mice.

[0062] like Figure 7 As shown, the results of brain tissue pathology examination showed that compared with the control group, the amyloid protein pathology of 5×FAD mice was significantly improved after intracerebroventricular injection of TALDO1 overexpression lentivirus, that is, increasing neuronal TALDO1 expression can reduce the deposition of amyloid plaques in the brain of 5×FAD mice and alleviate the amyloid protein pathology in the brain.

[0063] Based on the above results, it was further confirmed that targeting TALDO1 can effectively prevent and treat AD, and TALDO1 is an important target for AD.

[0064] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of a TALDO1 upregulator in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

2. The use according to claim 1, characterized in that: The TALDO1 up-regulator includes a substance that increases the expression level of TALDO1; and / or a substance that increases the activity and stability of TALDO1; and / or a substance that increases the effective action time of TALDO1.

3. The use according to claim 1, characterized in that: The TALDO1 up-regulator includes an RNA fragment complementary to the cDNA base sequence of TALDO1; or a nucleotide sequence, polypeptide, or protein that increases the expression of TALDO1; or a compound that increases the functional activity of TALDO1.

4. The use according to any one of claims 1 to 3, characterized in that: The TALDO1 up-regulator is a retrovirus that expresses an RNA segment complementary to the cDNA base sequence of TALDO1.

5. Use of the TALDO1 gene or its encoded protein as a target in the preparation of drugs for preventing and / or treating Alzheimer's disease.

6. The use according to claim 5, characterized in that: The drug has at least one of the following functions: a) promoting the activity and / or content of TALDO1; b) Reduce neuronal damage and synaptic disorders in Alzheimer's disease; c) Improve cognitive impairment in Alzheimer's disease model mice and / or Alzheimer's disease patients and delay the pathological progression of Alzheimer's disease.

7. The use according to claim 5, characterized in that: The drug comprises an effective amount of a neuron-specifically expressed TALDO1 upregulator, and a pharmaceutically acceptable carrier or excipient.

8. The use according to claim 7, characterized in that: The TALDO1 upregulator is used alone or in combination with a commercially available drug for preventing and / or treating Alzheimer's disease.

9. The use according to claim 5, characterized in that: The dosage form of the drug is selected from at least one of injection preparations, oral preparations, nasal drops, spray preparations, ointment preparations or patches.

10. Use of the TALDO1 gene or its encoded protein as a target in preparing a drug screening model for preventing and / or treating Alzheimer's disease.

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