Application of TAT-Pi4KII alpha fusion peptide in preparation of medicine for treating neurocognitive impairment

Abstract

The invention discloses an application of a TAT-Pi4KII alpha fusion peptide in preparation of a medicine for treating neurocognitive impairment. The TAT-Pi4KII alpha fusion peptide disclosed by the invention is as shown in SEQ ID No. 1 (sequence identifier number 1). Experiments prove that the TAT-Pi4KII alpha fusion peptide disclosed by the invention can relieve learning ability impairment, memory function impairment and space exploration cognitive ability impairment of animals with neurocognitive impairment. The TAT-Pi4KII alpha fusion peptide disclosed by the invention is used as an active ingredient for preparing a medicine for treating neurocognitive impairment, and has the advantages of quick effect, good curative effect and small side effect. The invention has great application value in treatment of neurocognitive impairment.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedicine, and relates to application of a TAT-Pi4KII alpha fusion peptide in preparation of a drug for treating neurocognitive disorders. BACKGROUND

[0002] Neurocognitive disorders (NCDs) are a kind of mental health disorders mainly affecting cognitive abilities (including learning, memory, language, thinking, spirit and emotion, etc.). According to the expression of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the main clinical manifestations of NCDs are cognitive ability defects such as executive function, learning and memory, perceptual-motor function, language, complex attention and social cognition, which are usually represented as decline, and are accompanied by underlying brain lesions. Neurocognitive disorder-related diseases include autism spectrum disorders (ASD), Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and traumatic brain injury (TBI), etc. Neurocognitive disorders are increasing the social and economic burden of the nation, and have become a major health problem that cannot be ignored by human beings, and therefore urgently need further attention. Therefore, it is urgent to study the pathogenesis of neurocognitive disorders and develop new treatment methods, which has important scientific significance and clinical value.

[0003] Phosphatidylinositol-4-kinase type II alpha subtype (Pi4KII alpha) is the most abundant phosphatidylinositol-4-kinase in mammals, is a key molecule in the phosphatidylinositol signaling pathway and phosphatidylinositol metabolism, and plays an important role in PI (4, 5) P2 biosynthesis, lysosome and Golgi-related membrane transport, intracellular signal transduction, pathogen phagocytosis and synaptic vesicle circulation, etc. In recent years, the functional research of Pi4KII alpha in nervous system diseases has been gradually reported. The function of Pi4KII alpha is closely related to diseases such as spastic paraplegia (Simons et al., Proc Natl Acad Sci USA, 2009), Alzheimer's disease (Kang et al., J Biol Chem, 2013) and post-traumatic stress disorder (Guo et al., iScience, 2020), making Pi4KII alpha an important potential drug target. However, there is no relevant report on the application of Pi4KII alpha and its fusion peptide in preventing and treating neurocognitive disorders. SUMMARY

[0004] The technical problem to be solved by the present application is how to treat neurocognitive disorders.

[0005] To solve the above technical problems, the present application first provides an application of a polypeptide in preparation of a product for treating and / or preventing neurocognitive disorders.

[0006] The polypeptide is A1), A2) or A3) as follows:

[0007] A1) a polypeptide having an amino acid sequence shown in SEQ ID No. 1 at positions 42-521;

[0008] A2) a polypeptide having an amino acid sequence shown in SEQ ID No. 1 at positions 42-521 in the sequence listing with substitution and / or deletion and / or addition of one or several amino acid residues and having the same function;

[0009] A3) a fusion polypeptide obtained by connecting a tag to the N terminus or / and C terminus of A1) or A2).

[0010] The protein in A2) above is a protein having 75% or more identity to the amino acid sequence of the protein shown in SEQ ID No. 1 at positions 45-521 and having the same function. The identity refers to the identity of the amino acid sequence. The identity of the amino acid sequence can be determined using a homology search site on the Internet, such as the BLAST page on the NCBI homepage. For example, the identity (%) can be obtained by searching the identity of a pair of amino acid sequences in Advanced BLAST 2.1 using blastp as the program, setting the Expect value to 10, setting all Filters to OFF, using BLOSUM62 as the Matrix, setting Gap existence cost, Per residue gap cost and Lambda ratio to 11, 1 and 0.85 (default values), respectively, and then calculating the identity of the amino acid sequence. The 75% or more identity refers to 75% identity, 80% identity, 85% identity, 90% identity, 95% identity, 96% identity, 97% identity, 98% identity or 99% identity.

[0011] The protein in A2) above can be artificially synthesized or can be obtained by first synthesizing the encoding gene and then performing biological expression.

[0012] The tag in A3) can be a polypeptide or protein that is fused and expressed together with the target protein by using DNA in vitro recombination technology, so as to facilitate the expression, detection, tracing and / or purification of the target protein. The tag can be Poly-Arg, Poly-His, FLAG, Strep-tag II, c-myc, MBP tag, HA tag, GST tag, SUMO tag and / or cell penetrating peptide TAT (GRKKRRQRRR), etc.

[0013] In one embodiment of the present application, the fusion polypeptide in A3) can be as shown in SEQ ID No. 1.

[0014] The polypeptide is also used in the treatment and / or prevention of neurocognitive disorders.

[0015] The present application also provides the use of biological materials related to the polypeptide in the preparation of products for the treatment and / or prevention of neurocognitive disorders; the biological materials are any of the following B1) to B7):

[0016] B1) a nucleic acid molecule encoding the polypeptide;

[0017] B2) an expression cassette containing the nucleic acid molecule of B1);

[0018] B3) a recombinant vector containing the nucleic acid molecule of B1), or an expression cassette containing the expression cassette of B2);

[0019] B4) a recombinant microorganism containing the nucleic acid molecule of B1), or an expression cassette containing the expression cassette of B2), or a recombinant microorganism containing the recombinant vector of B3);

[0020] B5) a transgenic animal cell line containing the nucleic acid molecule of B1), or an expression cassette containing the expression cassette of B2);

[0021] B6) a transgenic animal tissue containing the nucleic acid molecule of B1), or an expression cassette containing the expression cassette of B2);

[0022] B7) a transgenic animal organ containing the nucleic acid molecule of B1), or an expression cassette containing the expression cassette of B2).

[0023] The nucleic acid molecule can be DNA, such as cDNA, genomic DNA or recombinant DNA; the nucleic acid molecule can also be RNA, such as mRNA or hnRNA, etc.

[0024] Those artificially modified nucleotides with 75% or more identity to the nucleotide sequence of the polypeptide isolated from the present application, as long as they encode the polypeptide and have the same function, are derived from the nucleotide sequence of the present application and are equivalent to the sequence of the present application.

[0025] The term "identity" as used herein refers to sequence similarity with a natural nucleic acid sequence. The "identity" includes a nucleotide sequence having 75% or more, or 85% or more, or 90% or more, or 95% or more identity with the nucleotide sequence of the protein consisting of the amino acid sequence shown in positions 45-521 of SEQ ID No. 1 of the present application. The identity can be evaluated by naked eyes or computer software. Using computer software, the identity between two or more sequences can be expressed in percentage (%), which can be used to evaluate the identity between related sequences.

[0026] In the above application, the stringent conditions can be as follows: hybridization at 50℃ in a mixed solution of 7% sodium dodecyl sulfate (SDS), 0.5M NaPO4 and 1mM EDTA, and rinsing at 50℃ in 2xSSC, 0.1% SDS.

[0027] The 75% or more identity described above can be 80%, 85%, 90% or 95% or more identity.

[0028] In the above application, the expression cassette (polypeptide gene expression cassette) containing the nucleic acid molecule encoding the polypeptide described in B2) refers to a DNA capable of expressing the polypeptide in a host cell, which can include not only a promoter initiating the transcription of the polypeptide-encoding gene, but also a terminator terminating the transcription of the polypeptide-encoding gene. Further, the expression cassette can also include an enhancer sequence.

[0029] The recombinant vector containing the polypeptide gene expression cassette can be constructed using existing expression vectors.

[0030] In the above application, the vector can be a plasmid, cosmid, bacteriophage or viral vector.

[0031] In the above application, the microorganism can be yeast, bacteria, algae or fungi.

[0032] In the above application, the transgenic animal cell line, transgenic animal tissue and transgenic animal organ do not include reproductive material.

[0033] The use of the biological material in the treatment and / or prevention of neurocognitive disorders also falls within the scope of the present application.

[0034] The present application also provides a product for treating and / or preventing neurocognitive disorders, the active ingredient of which is the polypeptide or the biological material.

[0035] In the present application, the neurocognitive disorders can be manifested in learning ability, memory ability and / or cognitive ability.

[0036] Specifically, the neurocognitive disorder can be a neurocognitive disorder of a human or an animal. The animal can be a mammal. In an embodiment of the present application, the animal is a rat.

[0037] In the present application, the product can be a drug.

[0038] Experiments prove that the polypeptide of the present application can relieve the learning ability damage, memory function damage and spatial exploration cognitive ability damage of an animal with a neurocognitive disorder. Using the polypeptide of the present application as an active ingredient for preparing a drug for treating a neurocognitive disorder has the advantages of quick effect, good curative effect and small side effect. The present application has great application value for the treatment of a neurocognitive disorder.

[0039] The present application is further described in detail below with reference to the specific embodiments, and the examples given are only for illustrating the present application, rather than limiting the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not in any way constitute a limitation on the present application. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 Water maze positioning cruise experiment test results.

[0041] Figure 2 Water maze spatial exploration experiment test results.

[0042] Figure 3 Y maze experiment test results.

[0043] Figure 4 Effect of LPS intraperitoneal injection on expression of Pi4KIIa in the dorsal hippocampus of rats.

[0044] Figure 5 Effect of LPS intraperitoneal injection combined with TAT-Pi4KIIa brain microinjection on water maze positioning cruise experiment test.

[0045] Figure 6 Effect of LPS intraperitoneal injection combined with TAT-Pi4KIIa brain microinjection on water maze spatial exploration experiment test.

[0046] Figure 7 Effect of LPS intraperitoneal injection combined with TAT-Pi4KIIa brain microinjection on Y maze experiment test.

[0047] Figure 8 Effect of LPS intraperitoneal injection combined with TAT-Pi4KIIa brain microinjection on expression of Pi4KIIa in the dorsal hippocampus of rats. DETAILED DESCRIPTION

[0048] The present application adds His tag (HHHHHH) and cell penetrating peptide TAT (GRKKRRQRRR) to the C-terminal and N-terminal of Pi4KIIa respectively, constructs a polypeptide pcDNA3.1-TAT-Pi4KIIa (referred to as TAT-Pi4KIIa) with biological activity. The TAT-Pi4KIIa polypeptide is delivered into the target brain area by microinjection using the membrane penetration function of TAT, and is taken up by neurons in the brain to exert its biological function. The polypeptide TAT-Pi4KIIa of the present application has the following amino acid sequence:

[0049] MTSTLPFSPQVSTPRSKFKRISSEFAATMGRKKRRQRRRAHQGSDETSPLVSPERAQPPEYT

[0050] FPSVSGAHFPQVPGGAVRVAAAGSGPSPPCSPGHDRERQPLLDRARGAAAQGQTHTVAAQ

[0051] AQALAAQAAVAVHAVQTHRERNDFPEDPEFEVVVRQAEIAIECSIYPERIYQGSSGSYFVK

[0052] DSQGRIIAVFKPKNEEPYGNLNPKWTKWLQKLCCPCCFGRDCLVLNQGYLSEAGASLVDQ

[0053] KLELNIVPRTKVVYLASETFNYSAIDRVKSRGKRLALEKVPKVGQRFNRIGLPPKVGSFQL

[0054] FVEGYKDADYWLRRFEAEPLPENTNRQLLLQFERLVVLDYIIRNTDRGNDNWLIKYDYPM

[0055] DNPNCRDTDWVMVREPVIKVAAIDNGLAFPLKHPDSWRAYPFYWAWLPQAKVPFSQEIK

[0056] DLILPKISDPNFVKDLEEDLYELFKKDPGFDRGQFHKQIAVMRGQILNLTQALKDNKSPLHL

[0057] VQMPPVIVETARSHQRSSSESYTQSFQSRKPFFSWWGSHHHHHH (SEQ ID No. 1).

[0058] Pi4KIIa is shown in SEQ ID No. 1 at positions 45-521.

[0059] TAT-Pi4KIIa was synthesized by Nanjing Detai Biological Engineering Co., Ltd. The TAT-Pi4KIIa polypeptide was dissolved in physiological saline and diluted to the required concentration for brain region administration.

[0060] Experimental animals: SPF level Sprague-Dawley (SD) male rats (Guangdong Medical Experimental Animal Center, Animal Production License No. SCXK (Yue 2022-0002), body weight 180-200g, normal environment feeding.

[0061] Example 1, TAT-Pi4KIIa can alleviate LPS-induced cognitive impairment

[0062] I. LPS impairs the cognitive ability of rats and down-regulates the expression of Pi4KIIa in the dorsal hippocampus

[0063] Establishment of a model of neurocognitive disorder: After dissolving LPS with PBS, 2mg / kg LPS was injected intraperitoneally into SD male rats to induce the construction of a model of neurocognitive disorder (LPS group). Behavioral experiments were performed 24 hours after model establishment, including water maze experiment and Y maze experiment. Rats without any treatment served as controls (i.e. NC group).

[0064] Water maze experiment (Water maze): The water maze equipment used had a diameter of 1.6m and a height of 0.5m. The water temperature ranged from 25±1℃. The specific steps were as follows:

[0065] (1) Positioning cruise experiment: This experiment lasted for 4 days. Rats were placed in water from 4 quadrants in turn each day, with the rat's head facing the pool wall. The rat was allowed to freely explore in the pool, and the video capture and analysis system recorded the rat's swimming trajectory in real time. The time interval for each experiment was 15 minutes. If the rat did not find the hidden platform under the water within 60s, the rat was manually guided to the platform and stayed for 15s to facilitate the rat's memory of the location.

[0066] (2) Spatial exploration experiment: On the 5th day, the underwater platform was removed, and the experiment began 24h after the last training interval. The rat was gently placed in the water with its head facing the pool wall from the opposite side of the platform. The rat's movement trajectory within 60s was recorded, and the time spent in the target quadrant and other quadrants was recorded. This experiment mainly examines the rat's speed of crossing the platform and the time spent in the target quadrant, which is used to judge the rat's memory ability.

[0067] Y maze: Y maze consists of 3 arms of equal length (50 cm x 18 cm x 35 cm) with 120 degrees between each pair of arms. The start arm (the arm in which the rat begins exploration, always open), the novel arm (closed during the first trial and open during the second trial), and the other arm are randomly assigned. During the training phase, the novel arm is closed and the rat is allowed to explore the start arm and the other arm freely for 5 minutes. Two hours later, the rat is allowed to explore the three arms freely for 5 minutes in the retention test. The number of entries into the novel arm and the time spent in the novel arm are recorded.

[0068] The results show that in the place navigation experiment, the NC group of rats and the LPS group of rats gradually reduce the latency to find the platform hidden under the water surface after 4 days of swimming training Figure 1 A); the latency index of the NC group of rats is significantly lower than that of the LPS group on the 3rd and 4th days of training, indicating that LPS intraperitoneal injection inhibits the learning ability of rats Figure 1 A and B).

[0069] In the spatial exploration experiment, the LPS group of rats spent significantly less time in the target quadrant than the NC group, suggesting that the LPS group of rats had decreased memory function Figure 2 ).

[0070] In the Y maze experiment, the LPS group of rats spent significantly less time in the novel arm than the NC group, indicating that the spatial exploration cognitive ability of the LPS group of rats was significantly impaired Figure 3 ).

[0071] After 24 hours of LPS intraperitoneal injection, the microperforation method was used: after embedding the brain tissue, it was fixed on the sample head of the freezing microtome with a sample holder, and continuous sectioning was performed with a thickness of 50 μm. According to the rat brain stereotaxic atlas, when the target brain region is reached, use a 12 or 16 gauge sampling needle to perforate and remove the brain tissue, and place it in a pre-cooled EP tube for protein extraction and then perform Western blotting. The Anti-Pi4KIIα antibody used is a product of Santa Cruz Biotechnology Company; the anti-β-actin antibody is a product of Abways (Shanghai) Trading Co., Ltd.

[0072] The results of the Western blotting experiment are shown in Figure 4 Compared with the NC group, the expression of cytoplasmic Pi4KIIα in the dorsal hippocampus of the LPS group of rats was significantly down-regulated. The results show that Pi4KIIα is involved in LPS-induced neurocognitive impairment, and intervention of this molecule may rescue the cognitive impairment of rats.

[0073] II. Microinjection of TAT-Pi4KIIα into the brain can alleviate LPS-induced cognitive impairment

[0074] Stereotactic surgery of the brain nucleus: After anesthetizing the rats with an R550IP small animal anesthesia machine (Reward, China), they were placed in a prone position on the stereotactic frame and fixed horizontally with ear rods. The hair on the skull was shaved and the rats were fixed to the stereotactic frame; the surgical field was disinfected with iodine and 75% ethanol solution. The connective tissue of the rat's skull was cleaned, and the skull was exposed with arterial clamps. The anterior and posterior fontanelles were aligned. Four shallow holes were drilled on the surface of the skull with a skull drill, and small stainless steel screws were used to fix them. The cannula was inserted 1 mm above the target brain region (dorsolateral hippocampus). According to the rat's stereotactic mapping, the coordinates of the dorsal hippocampus were: AP, -3.8 mm; ML, ±2.5 mm; DV, -3.2 mm, where AP and ML are referenced to the anterior fontanelle, and DV is referenced to the skull surface. The cannula was fixed to the skull with dental cement, and a stainless steel inner core was inserted into the cannula to maintain patency and prevent infection. After the cement dried, the rats were removed from the positioning device and housed individually for 5-7 days to allow for recovery. During this period, they were given penicillin (200,000 IU, intraperitoneal injection) daily to prevent infection.

[0075] After the rats' weight recovered to the preoperative level, they were randomly divided into NC group, LPS group, and LPS+LPS+TAT-Pi4KIIα group. Both the LPS group and the LPS+TAT-Pi4KIIα group established a rat model of neurocognitive impairment by intraperitoneal injection of LPS (2 mg / kg). After modeling, the LPS+TAT-Pi4KIIα group received microinjection of the nucleus into the dorsal hippocampus 1 hour before training each day, while the LPS group received microinjection of an equal volume of physiological saline into the dorsal hippocampus 1 hour before training each day.

[0076] Nucleus microinjection: Clean the needle and PE tubing of the microinjector with deionized water and 75% ethanol solution, and air dry. Fill the needle and tubing with physiological saline to remove air bubbles from the drug delivery system. Before drawing up the drug, leave a small air bubble in the tubing to prevent the drug from mixing with the physiological saline. Connect the injection needle to the microinjector via the PE tubing, and adjust the needle length so that its tip extends 1 mm beyond the catheter to reach the target brain region (dorsolateral hippocampus in rats). The drug delivery time is 1 minute, after which the needle remains in place in the catheter for 1 minute to allow the drug to fully spread to the entire target brain region. The dosage is 1.0 μg / μL, and nucleus microinjection is performed into the dorsal hippocampus brain region 1 hour before training.

[0077] LPS (2 mg / kg) was administered via intraperitoneal injection for 24 hours, followed by microinjection into the nucleus. Swimming training for a positioning cruise experiment was then conducted 1 hour later, and this training continued for 4 days before a space exploration experiment. Results showed that in the positioning cruise experiment, after 4 days of swimming training, the latency period for finding the hidden platform beneath the water surface gradually decreased in the NC group, LPS group, and LPS+TAT-Pi4KIIα group. Figure 5(A); On days 2, 3, and 4 of training, the latency index of rats in the LPS group was significantly higher than that in the NC group and the LPS+TAT-Pi4KIIα group, and there was no significant difference between the NC group and the LPS+TAT-Pi4KIIα group, indicating that microinjection of TAT-Pi4KIIα into the brain region significantly alleviated LPS-induced learning impairment in rats. Figure 5 (A and B in the middle).

[0078] In the space exploration experiment, the time spent in the target quadrant by rats in the LPS group was significantly shorter than that in the NC group and the LPS+TAT-Pi4KIIα group, and there was no significant difference between the NC group and the LPS+TAT-Pi4KIIα group, suggesting that microinjection of TAT-Pi4KIIα into the brain region significantly alleviated LPS-induced memory impairment in rats. Figure 6 ).

[0079] LPS (2 mg / kg) was administered intraperitoneally, followed by microinjection into the brain nucleus 24 hours later. One hour later, the Y-maze test was performed. Results showed that the time spent in the new arm of the LPS group was significantly shorter than that of the NC group and the LPS+TAT-Pi4KIIα group, with no significant difference between the NC group and the LPS+TAT-Pi4KIIα group. This suggests that TAT-Pi4KIIα brain region microinjection significantly alleviates LPS-induced impairment of spatial exploration cognitive ability in rats. Figure 7 ).

[0080] Twenty-four hours after intraperitoneal injection of LPS, TAT-Pi4KIIα was microinjected into the dorsal hippocampus of rats at a dose of 1.0 μg / μL. One hour later, brain tissue was harvested using a microperforation method for immunoblotting. The results of the immunoblotting experiment are as follows: Figure 8 As shown, compared with the NC group, the expression of cytoplasmic Pi4KIIα in the dorsal hippocampus of rats in the LPS group was significantly downregulated, while TAT-Pi4KIIα microinjection significantly reversed the expression of cytoplasmic Pi4KIIα in the dorsal hippocampus of rats. These results validate the effectiveness of TAT-Pi4KIIα and indicate that upregulating Pi4KIIα expression in the dorsal hippocampus can serve as an effective treatment for neurocognitive impairment.

[0081] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. Application of peptides in the preparation of products for the treatment and / or prevention of neurocognitive impairment; The polypeptide is either A1), A2), or A3): A1) The amino acid sequence is the polypeptide from positions 45 to 521 of SEQ ID No. 1; A2) A polypeptide having the same function by substituting and / or deleting and / or adding one or more amino acid residues of the amino acid sequence shown in SEQ ID No. 1 in the sequence listing from position 45 to 521; A3) is a fusion peptide obtained by linking a tag to the N-terminus and / or C-terminus of A1) or A2).

2. The application according to claim 1, characterized in that: A3) The fusion polypeptide is shown in SEQ ID No.

1.

3. The use of the polypeptide described in claim 1 or 2 in the treatment and / or prevention of neurocognitive impairment.

4. The use of a biomaterial related to the polypeptide of claim 1 or 2 in the preparation of products for the treatment and / or prevention of neurocognitive impairment; said biomaterial is any one of B1) to B7) below: B1) A nucleic acid molecule encoding the polypeptide described in claim 1 or 2; B2) An expression cassette containing the nucleic acid molecule described in B1); B3) A recombinant vector containing the nucleic acid molecule described in B1), or a recombinant vector containing the expression cassette described in B2); B4) Recombinant microorganisms containing the nucleic acid molecules described in B1), or recombinant microorganisms containing the expression cassette described in B2), or recombinant microorganisms containing the recombinant vector described in B3); B5) A transgenic animal cell line containing the nucleic acid molecule described in B1), or a transgenic animal cell line containing the expression cassette described in B2); B6) Transgenic animal tissue containing the nucleic acid molecules described in B1), or transgenic animal tissue containing the expression cassette described in B2); B7) Transgenic animal organs containing the nucleic acid molecules described in B1) or transgenic animal organs containing the expression cassette described in B2).

5. The use of the biomaterial described in claim 4 in the treatment and / or prevention of neurocognitive impairment.

6. The application according to any one of claims 1-5, characterized in that: The neurocognitive impairments are manifested in learning ability, memory ability and / or cognitive ability.

7. The application according to any one of claims 1-6, characterized in that: The neurocognitive impairment refers to the neurocognitive impairment of a person or animal.

8. A product for treating and / or preventing neurocognitive disorders, wherein the active ingredient is the polypeptide of claim 1 or 2 or the biomaterial of claim 4.

9. The product according to claim 8, characterized in that: The neurocognitive impairments are manifested in learning ability, memory ability and / or cognitive ability.

10. The product according to claim 8 or 9, characterized in that: The neurocognitive impairment refers to the neurocognitive impairment of a person or animal.

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