Application of cobicistat in preparation of medicine for treating diseases caused by Tau excessive phosphorylation

Abstract

The invention discloses application of cobicistat in preparation of a medicine for treating diseases caused by Tau excessive phosphorylation, and belongs to the technical field of biology. The cobicistat can reduce Tau protein excessive phosphorylation at the early stage of the disease by inducing CD44 positive microglial cell proliferation at the early stage of the Tau disease, and effectively improves spatial cognitive impairment. The cobicistat has a remarkable effect on Tau protein phosphorylation and cognitive impairment after being continuously treated for 2 months, and lays a foundation for a treatment means for clinically treating diseases caused by Tau excessive phosphorylation.

Description

Technical Field

[0001] The present invention belongs to the field of biotechnology, and more specifically, relates to the use of corisvastat in the preparation of a medicament for treating diseases caused by hyperphosphorylation of Tau. Background Art

[0002] Tauopathies are a group of neurodegenerative diseases characterized by abnormal deposition of Tau protein, and their core pathological manifestations are the formation of neurofibrillary tangles (NFTs) and paired helical filaments (PHFs) in neurons and glial cells. Such diseases include Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), etc., accounting for 10%-20% of global dementia cases. Among them, there are more than 55 million AD patients, and the prevalence rates of PSP and FTD are 5-7 / 100,000 and 15-22 / 100,000 respectively. Tau protein is encoded by the MAPT gene. Under normal circumstances, it maintains axonal transport and structural integrity of neurons by stabilizing microtubules. However, in pathological conditions, conformational changes occur due to post-translational modifications such as hyperphosphorylation and acetylation, forming a β-sheet structure and abnormally aggregating, thereby losing the microtubule-binding ability, leading to axonal transport disorders and synaptic damage. This abnormally aggregated Tau protein has prion-like properties and can spread between neurons and induce misfolding of normal Tau protein, forming a cascade of pathological effects. Genetic factors such as MAPT gene mutations and H1 haplotypes are closely related to the susceptibility to 4R-Tau diseases, while environmental factors such as neuroinflammation, oxidative stress, and repetitive traumatic brain injury (rTBI) exacerbate Tau phosphorylation by activating the NF-κB and MAPK pathways. The pathological features show regional selectivity. For example, AD mainly affects the hippocampus and temporal lobe, PSP involves the basal ganglia and brainstem, and FTD is concentrated in the frontotemporal cortex. The distribution of Tau isoforms varies significantly among different diseases (such as the 3R / 4R mixed type in AD and the 3R type in Pick's disease). The clinical manifestations include cognitive impairment (such as memory decline in AD and executive function decline in FTD), movement disorders (such as supranuclear ophthalmoplegia in PSP), and mental symptoms (such as emotional outbursts in CTE). Current treatments face multiple challenges: the diversity of Tau protein isoforms (6 subtypes) and the complexity of modification sites (more than 45 phosphorylation sites) make it difficult for a single target to cover all pathologies; the blood-brain barrier limits the drug delivery efficiency, and antibody drugs such as semorinemab have limited efficacy due to low brain penetration; there is a disconnect between biomarkers and clinical endpoints in clinical trials. For example, bepranemab can reduce Tau burden but fails to improve cognitive scores. In addition, the lack of early diagnostic tools results in patients being in an irreversible stage of nerve damage when they are enrolled.

[0003] CD44-positive microglia are a subset of immune cells expressing CD44 receptors in the central nervous system, playing dual roles in neuroinflammation, tissue repair, and immune regulation. These cells interact with monocytes or other immune cells through signaling axes such as OPN-CD44 or LGALS9-CD44, promoting a pro-inflammatory microenvironment (e.g., exacerbating nerve injury in intracerebral hemorrhage) and driving the repair process (e.g., promoting nerve regeneration and angiogenesis after ischemic stroke). Their functional dynamics are affected by pathological states. For example, resting microglia can be activated to the CD44-positive state in hypoxia or neurodegenerative diseases, releasing inflammatory factors or enhancing phagocytic function. At the molecular level, CD44 binds to ligands such as hyaluronic acid and osteopontin, regulating signaling pathways such as NF-κB and mediating the balance between inflammation and repair. Recent studies have revealed their heterogeneity through single-cell sequencing and explored targeting CD44-related pathways (e.g., inhibiting OPN-CD44 or delivering LGALS9) as potential strategies for treating diseases such as intracerebral hemorrhage and stroke, providing a new direction for neuroimmune regulation.

[0004] Cobicistat (chemical formula: C 40 H 53 N7O5S2) is a drug analogue of the antiretroviral drug ritonavir. The replacement of its valine part with 2-morpholinoethyl and the removal of the backbone hydroxyl group optimize it into a potent CYP3A inhibitor lacking anti-HIV activity. As one of the most important metabolic enzyme subfamilies in the cytochrome P450 superfamily, CYP3A is mainly responsible for the metabolism of drugs and exogenous substances. Therefore, cobicistat can increase the overall absorption of various HIV drugs and prolong the efficacy of antiviral drugs by inhibiting intestinal transporters and the metabolism of certain antiviral drugs. Cobicistat is usually used as a component of drugs for treating HIV. For example, when combined with elvitegravir, it can increase the plasma concentration of other co-administered anti-HIV drugs and avoid drug-resistant mutations that cause cobicistat resistance in the HIV virus. As it has long been widely used clinically to enhance the blood drug concentration of other antiretroviral drugs (such as HIV protease inhibitors), as the first approved "pure enhancer", its side effects are relatively mild and limited.

[0005] Currently, the treatment of diseases caused by Tau hyperphosphorylation uses trial-dependent cognitive scales (such as ADAS-Cog) as the main endpoint. However, Tau pathology starts 10 - 20 years before the onset of symptoms, and most trials enroll patients in the middle and late stages, resulting in the technical problem of a lag in the intervention window period due to the misalignment. Summary of the Invention

[0006] The object of the present invention is to provide the use of corisvastat in the preparation of a medicament for treating diseases caused by hyperphosphorylated Tau. Corisvastat reduces the hyperphosphorylation of Tau protein at the early stage of the disease by inducing the proliferation of CD44-positive microglia, thereby shifting the treatment window forward to the stage of mild cognitive impairment (MCI), and solving the problem of the lag in the intervention timing of diseases caused by current hyperphosphorylated Tau.

[0007] According to the object of the present invention, there is provided the use of corisvastat in the preparation of a medicament for treating diseases caused by hyperphosphorylated Tau. The chemical formula of the corisvastat is: C 40 H 53 N7O5S2, and the structural formula is:

[0008]

[0009] Preferably, the corisvastat reduces the hyperphosphorylation of Tau protein by inducing the proliferation of CD44-positive microglia.

[0010] Preferably, the diseases caused by hyperphosphorylated Tau are primary Tauopathy, secondary Tauopathy, hereditary Tauopathy or atypical Tauopathy.

[0011] Preferably, the primary Tauopathy is Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial Tauopathy, primary age-related Tauopathy, behavioral variant frontotemporal dementia or age-related Tau astrogliopathy.

[0012] Preferably, the secondary Tauopathy is Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, amyotrophic lateral sclerosis-frontotemporal dementia or vascular dementia complicated with Tau disease.

[0013] Preferably, the hereditary Tauopathy is familial frontotemporal dementia or hereditary progressive supranuclear palsy.

[0014] Preferably, the atypical Tauopathy is chronic traumatic encephalopathy, Tauopathy associated with prion disease or argyrophilic grain disease.

[0015] Generally speaking, compared with the prior art through the above technical solutions conceived by the present invention, the following technical advantages are mainly possessed:

[0016] (1) Compared with wild-type (WT) mice, Tau is hyperphosphorylated in the entorhinal cortex (EC) of Tauopathy model mice (P301L), and significant cognitive impairment occurs. By performing single-nucleus sequencing on the EC brain region of 2-month-old P301L mice in the early stage of the disease, it was found that CD44-positive microglia proliferate and play an important regulatory role in spatial cognitive function. The present invention first discovers that in the early stage of the disease, CD44-positive microglia play an important role in reducing Tau phosphorylation and improving the spatial cognitive ability of mice.

[0017] (2) The present invention provides the use of cobicistat in the preparation of therapeutic drugs for Tauopathy and related cognitive impairment diseases. Cobicistat mainly induces the proliferation of CD44-positive microglia in the early stage of Tauopathy, thereby reducing the hyperphosphorylation of Tau protein in the early stage of the disease and effectively improving the spatial cognitive impairment in mice. After continuous treatment with cobicistat for 2 months, it has a significant effect on Tau protein phosphorylation and cognitive impairment. It provides an important basis for the early treatment of Tauopathy and related cognitive impairment diseases and has broad clinical application value.

[0018] (3) Based on the unique structural characteristics of the amino acid sequence at positions 79-99 of the CD44 protein, the present invention first adopts a structure-guided virtual screening strategy and successfully develops a new use of cobicistat as a therapeutic drug for Tauopathy targeting CD44.

[0019] (4) The present invention provides the application of cobicistat in the preparation of drugs for treating diseases caused by Tau hyperphosphorylation. Cobicistat can significantly slow down the phosphorylation of Tau protein and the occurrence and development of cognitive impairment in the P301L model. As a co-drug for HIV protease inhibitors, its known pharmacokinetic properties (half-life 3.5 h, protein binding rate 98%) can accelerate clinical translation. Brief Description of the Drawings

[0020] Figure 1 Shows the conservation of 79-99AA of the CD44 molecule in mammals.

[0021] Figure 2 Shows the efficiency of the drug in inducing the proliferation of CD44-positive microglia at the cellular level. (Statistical chart mean±SEM, *p<0.05, **p<0.01, ****p<0.0001, n = 6, scale bar = 20 μm)

[0022] Figure 3 Shows the visualization of ligand-receptor interaction.

[0023] Figure 4To detect the level of CD44 expression induced by cobicistat in microglia by immunofluorescence. (A. Immunofluorescence labeling method was used to evaluate the content of CD44. Green fluorescence labeled Iba1, red fluorescence labeled CD44, and blue fluorescence labeled Dapi. Scale bar = 20 μm. B. Statistical analysis result chart of CD44 fluorescence intensity, mean±SEM, ****p<0.0001, n = 6)

[0024] Figure 5 This is the immunofluorescence image of improving the expression of CD44 protein in microglia in the EC brain region of mice in the examples of the present invention. (A. Immunofluorescence labeling method was used to evaluate the content of CD44. Green fluorescence labeled Iba1, red fluorescence labeled CD44, and blue fluorescence labeled Dapi. Scale bar = 20 μm. B. Statistical analysis result chart of CD44 fluorescence intensity, mean±SEM, ****p<0.0001, n = 6)

[0025] Figure 6 This is the immunofluorescence image of improving Tau lesions in the EC brain region of mice in the examples of the present invention. (A. Immunofluorescence labeling method was used to evaluate the content of AT8. Blue fluorescence labeled Dapi, green fluorescence labeled AT8. Scale bar = 20 μm. B. Statistical analysis result chart of AT8 fluorescence intensity, mean±SEM, ****p<0.0001, n = 6)

[0026] Figure 7 This is the statistical chart of behavioral data for improving learning and memory impairment in mice in the examples of the present invention. (Statistical chart mean±SEM, *p<0.05, **p<0.01, ****p<0.0001, n = 8) Detailed implementation manners

[0027] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other. In the following quantitative tests, three repeated experiments were set, and the results were averaged.

[0028] In this invention, the Tau phosphorylation levels were measured and the learning and cognitive impairments were evaluated in the EC brain regions of 2-month-old male and female P301L and WT mice. It was found that in P301L mice, the Tau phosphorylation level in female mice was more severe than that in male mice, and the cognitive impairment appeared earlier, while there was no obvious change in the WT group. Further, single-nucleus (SnRNA) sequencing was performed on the EC brain regions of 2-month-old male and female mice to comprehensively map the transcriptional profiles of male and female mice in the early stage of AD. The analysis found that CD44-positive microglia were more expressed in male mice, while rarely in female mice. The researchers knocked out the CD44 gene expression in microglia using gene editing technology and found that male mice expressed similar Tau phosphorylation levels and learning and cognitive impairments as female mice. This indicates the key role of CD44-positive microglia in reducing Tau phosphorylation levels and learning and cognitive impairments, and further supports the drug research targeting the activation of this molecule, thus providing help for improving the symptoms of Tau proteinopathy and related cognitive impairment diseases.

[0029] The following are specific examples

[0030] Example 1: Verification of the conservation of CD44 molecule in mammals

[0031] In this example, the MUSCLE algorithm of MEGA 11 was used to align the designated sequences (79-99AA) of human (NP_000601.3), mouse (NP_001034240.1), brown rat (NP_037056.3), cattle (NP_776438.2), dog (NP_001183951.1), horse (NP_001078904.2), and hamster (NP_001268802.1) in the NCBI database. The parameter settings were: substitution model JTT, gap handling Pairwise deletion, and Bootstrap test 1000 times. And a phylogenetic tree in mammals was drawn.

[0032] The above results show that among mammals, the amino acid sequence region at positions 79-99 of the CD44 molecule has high conservation. The results are as Figure 1 shown.

[0033] Example 2: Prediction of a list of small molecule drugs by molecular docking strategy

[0034] In this example, the crystal structure of the CD44 protein (such as PDB: 2JCP) was obtained from the PDB database. The crystallization water was removed, the missing residues were supplemented, and polar hydrogen atoms were added through the "Prepare Protein" module of Discovery Studio. Based on the CD44 hyaluronic acid binding domain (79-99AA) and the intracellular tail ankyrin binding domain, the spherical binding pocket was defined using the "Receptor-Ligand Interactions" tool.

[0035] The 5,671 small molecule libraries approved by the FDA in the ZINC15 database were loaded, and high-throughput docking was performed through the LibDock module, generating 517,603 complexes, and the physical complementarity of each pose with the CD44 pocket was scored.

[0036] We selected the top 100 complexes for analysis and chose 20 commercial compounds for further biological experiments. Table 1 below lists the Zinc_id, Libdock score, Molecule name, and commercial item number corresponding to the top 100 complexes.

[0037] Table 1

[0038]

[0039]

[0040] Example 3: Detecting the proliferation effect of each drug on CD44-positive microglia

[0041] In this example, different drugs were added to BV2 cells respectively, and the PBS treatment group was set as a negative control. After 24 hours of drug treatment, after termination of the treatment, the cells were digested with 0.25% trypsin + Accutase (1:1 mixture) to avoid over-digestion damage to surface antigens. The digested cell suspension was filtered through a 40 μm filter to remove cell clumps. Washed twice with pre-cooled PBS (300 g × 5 min), resuspended in PBS buffer containing 2% FBS, and adjusted to a density of 1×10 6 cells / mL. 100 μL of cell suspension was added to each tube, and Fc blocker (such as anti-mouse CD16 / 32 antibody) was added and incubated for 10 min to reduce non-specific binding. CD44-PE / Cy7 antibody was added (incubated on ice in the dark for 30 min). After washing, FVS was added to distinguish dead cells to avoid false positive signals.

[0042] Finally, data on the conversion efficiency of all drugs (the drugs in Example 2) to induce CD44-positive microglia were obtained through the analysis of the CD44-PE / Cy7 high-expression population. Cobicistat had the most significant induction effect, reaching 30%.

[0043] The experimental results showed that 5 drugs (Deferoxamine, Cobicistat, Naloxegol, Saquinavir, and Fosaprepitant) could induce CD44 ++ the proportion of microglia to increase, 10 drugs had no obvious effect, and 4 drugs induced CD44 -The phenotype increased, and another drug was cytotoxic. We further analyzed the above five positive drugs in depth. Although Fosaprepitant can bind to CD44 through its phosphate group, it is rapidly hydrolyzed in vivo to Aprepitant lacking the phosphate group and cannot achieve stable binding; Saquinavir lacks effective blood-brain barrier penetration ability; Naloxegol, as a peripheral opioid receptor antagonist, was designed to specifically reduce central penetration to avoid affecting analgesia. Deferoxamine has been reported more in the treatment of AD and can be used as a positive control. Therefore, Cobicistat was finally selected as the most promising candidate drug with relatively low drug side effects. The results are as Figure 2 shown.

[0044] Example 4: Visualization of the interaction between Cobicistat ligand and CD44 receptor

[0045] In this example, the "Electrostatic Surface" tool was used to show that the CD44 binding pocket was strongly negatively charged (green area), while the binding site of Cobicistat was positively charged (purple area), forming charge complementarity between the two.

[0046] The experimental results showed that CD44 and Cobicistat had good physical complementarity. The results are as Figure 3 shown.

[0047] Example 5: Detection of the efficiency of Cobicistat in inducing CD44 protein expression in microglia

[0048] In this example, the induction efficiency of CD44-positive microglia was quantified by immunofluorescent staining of BV2 microglia treated with Cobicistat.

[0049] We added Cobicistat to BV2 cells and set the PBS treatment group as the negative control. After 24 hours of drug treatment, the treatment was terminated, and the cells were washed twice with pre-cooled PBS, followed by a cell immunostaining experiment. The steps are as follows: permeabilize the cell slides with 0.5% Triton X-100 (vol / vol) for 20 min, and incubate them in a blocking solution containing 3% bovine serum albumin (BSA, SX-100) and 0.1% phosphate-buffered saline (PBS) at room temperature for 30 min. Then, the sections were incubated overnight at 4 °C in a mixture of primary antibody containing CD44 (PBS containing 3% BSA and 0.1% Triton X-100). Then, the sections were rinsed 3 times with PBS, and then incubated with a fluorescence-conjugated secondary antibody (1:500) at 37 °C for 1 hour, and DAPI was added to observe the cell nuclei. Images were obtained using a Zeiss LSM800 laser confocal microscope (Zeiss, Jena, Germany).

[0050] The experiment found that the expression of CD44 in BV2 cells in the Cobicistat treatment group was higher than that in the PBS treatment group, and the results were as Figure 4 shown. The experimental results showed that Cobicistat could induce the proliferation of CD44-positive microglia.

[0051] Example 6: Cobicistat improves the expression of CD44 in microglia in the EC brain region of mice

[0052] The previous experimental results showed that in the P301L model, the Tau lesions in female mice were more severe than those in male mice, and learning and memory impairments appeared earlier. The EC brain region of P301L female mice treated with Cobicistat was immunofluorescently stained to quantify the proliferation changes of CD44-positive microglia.

[0053] Female P301L mice were fed with cobicistat drug and its control saline, 30 mg / Kg.d, intraperitoneally injected 3 times a week, with six mice in each group. After 2 months, perfusion, tissue sampling and immunostaining experiments were carried out. The steps are as follows: Free-floating brain slices were permeabilized with 0.5% Triton X-100 (vol / vol) for 20 min, and incubated in a blocking solution containing 3% bovine serum albumin (BSA, SX-100) and 0.1% phosphate buffered saline (PBS) at room temperature for 30 min. Then, the slices were incubated overnight at 4 °C in a mixture of primary antibodies containing CD44 and Iba1 (PBS containing 3% BSA and 0.1% Triton X-100). Then, the slices were rinsed 3 times with PBS, and then incubated with the respective fluorescence-conjugated secondary antibodies (1:500) at 37 °C for 1 hour, and DAPI was added to observe the cell nuclei. Images were obtained using a Zeiss LSM800 laser confocal microscope (Zeiss, Jena, Germany).

[0054] The experiment found that the number of CD44-positive microglia in the cobicistat treatment group was larger than that in the saline treatment group. The results are as Figure 5 shown. The experimental results show that cobicistat can induce the proliferation of CD44-positive microglia in animals.

[0055] Example 7: Cobicistat improves Tau lesions in the EC brain region of mice

[0056] In this example, the expression changes of AT8 were quantified by immunofluorescence staining of the EC brain region of P301L female mice treated with cobicistat.

[0057] Female P301L mice were fed with cobicistat drug and its control saline, 30 mg / Kg.d, intraperitoneally injected 3 times a week, with six mice in each group. After 2 months, perfusion, tissue sampling and immunostaining experiments were carried out. The steps are as follows: Free-floating brain slices were permeabilized with 0.5% Triton X-100 (vol / vol) for 20 min, and incubated in a blocking solution containing 3% bovine serum albumin (BSA, SX-100) and 0.1% phosphate buffered saline (PBS) at room temperature for 30 min. Then, the slices were incubated overnight at 4 °C in a mixture of primary antibodies containing AT8 (PBS containing 3% BSA and 0.1% Triton X-100). Then, the slices were rinsed 3 times with PBS, and then incubated with the respective fluorescence-conjugated secondary antibodies (1:500) at 37 °C for 1 hour, and DAPI was added to observe the cell nuclei. Images were obtained using a Zeiss LSM800 laser confocal microscope (Zeiss, Jena, Germany).

[0058] Experimental findings showed that compared with the normal saline treatment group, the AT8 expression in the EC brain region of the Cobicistat treatment group was lower. The results are as Figure 6 shown. The experimental results indicate that Cobicistat can inhibit the hyperphosphorylation of Tau in animals.

[0059] Example 8: Cobicistat Improves Learning and Memory Impairment in Mice

[0060] In this example, through behavioral experiments related to learning and memory (Barnes maze, water maze, etc.), it was confirmed that Cobicistat can improve learning and memory impairment in mice.

[0061] Two-month-old P301L female mice were fed with Cobicistat drug and its control normal saline, 30 mg / Kg.d, intraperitoneally injected, three times a week, with six mice in each group. After 2 months, we conducted behavioral experiments related to learning and memory on the mice. The specific steps are as follows:

[0062] Water maze experiment: A circular pool was filled with opaque water, and a hidden platform was placed in a quadrant below the water surface. The movement of the mice was recorded using a digital tracking device. Briefly, these mice were trained to find the hidden platform for 6 consecutive days, with 3 trials per day. On the 8th day, a probe test was conducted to test spatial memory. The hidden platform was removed, and the ability of the mice to find the platform position within 90 seconds starting from the opposite quadrant was tested. The escape latency to the previous position of the platform was measured, and the percentage of time spent in each quadrant was analyzed.

[0063] Barnes maze experiment: The Barnes maze consists of a white disc (100 cm in diameter), and 18 holes are evenly placed on an equidistant circle. The escape box is placed under one of the holes. The mice learn the position of the escape box under the hole through spatial reference points fixed on the wall. The animals were given one trial in the Barnes maze. The training included placing the animals in a black box. Then, the mice freely explored the maze to find the escape box under the hole. The maximum delay to find the escape box was 300 seconds. The latency to reach the escape box and the number of incorrect holes were measured. After the first day of training, the test began, and data from two trials were recorded over the next 3 days. On the 5th day, the escape box was removed, and each mouse was placed in the center of the maze. The number of attempts to find the escape box, the delay to reach the target hole, and the number of other holes were all evaluated by an experimenter without regard to group information.

[0064] It was found that compared with the normal saline group, the mice in the Cobicistat group showed stronger learning and memory abilities in the water maze experiment, with a shorter latency to find the target area and a higher frequency; in the Barnes maze experiment, the latency to find the target area was shorter and the correct rate was higher. The results are as Figure 7 shown. The experimental results indicate that Cobicistat can improve the spatial learning and cognitive impairment in the P301L mouse model.

[0065] Those skilled in the art can easily understand that the above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of corisvastat in the preparation of a drug for treating diseases caused by Tau hyperphosphorylation, the chemical formula of said corisvastat: C 40 H 53 N7O5S2, and the structural formula is:

2. The application according to claim 1, wherein The coprobustat reduces the hyperphosphorylation of Tau protein by inducing the proliferation of CD44-positive microglia.

3. The application according to claim 1, characterized in that The diseases caused by the Tau hyperphosphorylation are primary Tauopathy, secondary Tauopathy, hereditary Tauopathy or atypical Tauopathy.

4. The application according to claim 3, characterized in that The primary Tauopathy is Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial Tauopathy, primary age-related Tauopathy, behavioral variant frontotemporal dementia or aging-related Tau astrogliopathy.

5. The application according to claim 3, wherein The secondary Tauopathy is Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, amyotrophic lateral sclerosis-frontotemporal dementia or vascular dementia complicated with Tau disease.

6. The application according to claim 3, characterized in that The hereditary Tauopathy is familial frontotemporal dementia or hereditary progressive supranuclear palsy.

7. The application according to claim 3, characterized in that The atypical Tauopathy is chronic traumatic encephalopathy, Tauopathy associated with prion disease or argyrophilic grain disease.

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