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CNS Drug Action in Neurodegenerative Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 33048

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Special Issue Editor

Prof. Dr. Stefanie Kürten

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Guest Editor

Institute of Neuroanatomy, Faculty of Medicine, University of Bonn, 53115 Bonn, Germany
Interests: autoimmunity; autoantibodies; B cells; EAE; multiple sclerosis; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s, and Parkinson’s disease are neurodegenerative diseases of the central nervous system, which represent a major socioeconomic burden to society. All of these diseases are similar in that their etiology is still unclear and there are different theories on their pathogenesis. While most drugs that are approved to treat neurodegeneration are able to reduce clinical symptoms and slow down disease progression, they cannot cure the disease. In addition, the availability of suitable biomarkers that could predict treatment success is very limited, so that patient-oriented therapy has remained a future goal. Yet, intensive research is ongoing to eventually unravel the mechanisms underlying neurodegeneration and central nervous system repair. This open-access Special Issue will bring together original research and review articles on the mode of action of different drugs that were designed to limit neurodegeneration, support neuroprotection, and/or to promote neural repair, highlighting what has already been achieved and which new discoveries, approaches, and technical developments in central nervous system research are on their way.

Topics of this Special Issue include but are not limited to:

- Etiology and pathogenesis of neurodegenerative diseases;

- Mechanisms of neurodegeneration, neuroprotection, and neural repair in the central nervous system;

- Pharmaceutical and pharmacological central nervous system drug classification;

- Mode of action of central nervous system drugs;

- Past and ongoing clinical trials using CNS drugs in neurodegenerative diseases;

- Novel strategies for the prevention and treatment of CNS degeneration.

Prof. Dr. Stefanie Kürten
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

CNS drugs
neurodegenerative diseases
neuroprotection
neuroregeneration
pharmacology

Published Papers (10 papers)

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Research

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15 pages, 3883 KiB

Open AccessArticle

Neuroprotective Effects of Erinacine A on an Experimental Model of Traumatic Optic Neuropathy

by Chiao-Ling Hsu, Yao-Tseng Wen, Tzu-Chao Hsu, Chin-Chu Chen, Li-Ya Lee, Wan-Ping Chen and Rong-Kung Tsai

Int. J. Mol. Sci. 2023, 24(2), 1504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021504 - 12 Jan 2023

Viewed by 2415

Abstract

Erinacine A (EA), a natural neuroprotectant, is isolated from a Chinese herbal medicine, Hericium erinaceus. The aim of this study was to investigate the neuroprotective effects of EA in a rat model of traumatic optic neuropathy. The optic nerves (ONs) of adult male Wistar rats were crushed using a standardized method and divided into three experimental groups: phosphate-buffered saline (PBS control)-treated group, standard EA dose-treated group (2.64 mg/kg in 0.5 mL of PBS), and double EA dose-treated group (5.28 mg/kg in 0.5 mL of PBS). After ON crush, each group was fed orally every day for 14 days before being euthanized. The visual function, retinal ganglion cell (RGC) density, and RGC apoptosis were determined using flash visual-evoked potentials (fVEP) analysis, retrograde Fluoro-Gold labelling, and TdT-dUTP nick end-labelling (TUNEL) assay, respectively. Macrophage infiltration of ON was detected by immunostaining (immunohistochemistry) for ED1. The protein levels of phosphor-receptor-interacting serine/threonine-protein kinase1 (pRIP1), caspase 8 (Cas8), cleaved caspase 3 (cCas3), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor1 (TNFR1), interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and superoxide dismutase 1 (SOD1) were evaluated by Western blotting. When comparing the standard EA dose-treated group and the double EA dose-treated group with the PBS-treated group, fVEP analysis showed that the amplitudes of P1–N2 in the standard EA dose group and the double EA dose-treated group were 1.8 and 2.4-fold, respectively, higher than that in the PBS-treated group (p < 0.05). The density of RGC in the standard EA dose-treated group and the double EA dose-treated group were 2.3 and 3.7-fold, respectively, higher than that in the PBS-treated group (p < 0.05). The TUNEL assay showed that the standard EA dose-treated group and the double EA dose-treated group had significantly reduced numbers of apoptotic RGC by 10.0 and 15.6-fold, respectively, compared with the PBS-treated group (p < 0.05). The numbers of macrophages on ON were reduced by 1.8 and 2.2-fold in the standard EA dose-treated group and the double EA dose-treated group, respectively (p < 0.01). On the retinal samples, the levels of pRIP, Cas8, cCas3, TNF-α, TNFR1, IL-1β, and iNOS were decreased, whereas those of Nrf2, HO-1, and SOD1 were increased in both EA-treated groups compared to those in the PBS-treated group (p < 0.05). EA treatment has neuroprotective effects on an experimental model of traumatic optic neuropathy by suppressing apoptosis, neuroinflammation, and oxidative stress to protect the RGCs from death as well as preserving the visual function. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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28 pages, 7662 KiB

Open AccessArticle

Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis

by Alicia Weier, Michael Enders, Philipp Kirchner, Arif Ekici, Marc Bigaud, Christopher Kapitza, Jürgen Wörl and Stefanie Kuerten

Int. J. Mol. Sci. 2022, 23(22), 14209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214209 - 17 Nov 2022

Viewed by 2063

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphate receptor modulator siponimod is the only approved drug for SPMS. In the pivotal trial, siponimod reduced disease progression and brain atrophy compared with placebo. The enteric nervous system (ENS) was recently identified as an additional autoimmune target in MS. We investigated the effects of siponimod on the ENS and CNS in the experimental autoimmune encephalomyelitis model of MS. Mice with late-stage disease were treated with siponimod, fingolimod, or sham. The clinical disease was monitored daily, and treatment success was verified using mass spectrometry and flow cytometry, which revealed peripheral lymphopenia in siponimod- and fingolimod-treated mice. We evaluated the mRNA expression, ultrastructure, and histopathology of the ENS and CNS. Single-cell RNA sequencing revealed an upregulation of proinflammatory genes in spinal cord astrocytes and ependymal cells in siponimod-treated mice. However, differences in CNS and ENS histopathology and ultrastructural pathology between the treatment groups were absent. Thus, our data suggest that siponimod and fingolimod act on the peripheral immune system and do not have pronounced direct neuroprotective effects. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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19 pages, 5466 KiB

Open AccessArticle

Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke

by Erika Meyer, Phillip Rieder, Davide Gobbo, Gabriella Candido, Anja Scheller, Rúbia Maria Weffort de Oliveira and Frank Kirchhoff

Int. J. Mol. Sci. 2022, 23(21), 12886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112886 - 25 Oct 2022

Cited by 5 | Viewed by 2560

Abstract

Pharmacological agents limiting secondary tissue loss and improving functional outcomes after stroke are still limited. Cannabidiol (CBD), the major non-psychoactive component of Cannabis sativa, has been proposed as a neuroprotective agent against experimental cerebral ischemia. The effects of CBD mostly relate to the modulation of neuroinflammation, including glial activation. To investigate the effects of CBD on glial cells after focal ischemia in vivo, we performed time-lapse imaging of microglia and astroglial Ca²⁺ signaling in the somatosensory cortex in the subacute phase of stroke by in vivo two-photon laser-scanning microscopy using transgenic mice with microglial EGFP expression and astrocyte-specific expression of the genetically encoded Ca²⁺ sensor GCaMP3. CBD (10 mg/kg, intraperitoneally) prevented ischemia-induced neurological impairment, reducing the neurological deficit score from 2.0 ± 1.2 to 0.8 ± 0.8, and protected against neurodegeneration, as shown by the reduction (more than 70%) in Fluoro-Jade C staining (18.8 ± 7.5 to 5.3 ± 0.3). CBD reduced ischemia-induced microglial activation assessed by changes in soma area and total branch length, and exerted a balancing effect on astroglial Ca²⁺ signals. Our findings indicate that the neuroprotective effects of CBD may occur in the subacute phase of ischemia, and reinforce its strong anti-inflammatory property. Nevertheless, its mechanism of action on glial cells still requires further studies. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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13 pages, 1582 KiB

Open AccessArticle

New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease

by María Almudena Coto-Vilcapoma, Juan Castilla-Silgado, Benjamín Fernández-García, Paola Pinto-Hernández, Raffaela Cipriani, Estibaliz Capetillo-Zarate, Manuel Menéndez-González, Marco Álvarez-Vega and Cristina Tomás-Zapico

Int. J. Mol. Sci. 2022, 23(16), 9256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169256 - 17 Aug 2022

Cited by 5 | Viewed by 2340

Abstract

We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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16 pages, 2567 KiB

Open AccessArticle

The Memory Benefit to Aged APP/PS1 Mice from Long-Term Intranasal Treatment of Low-Dose THC

by Oksana Fihurka, Yuzhu Hong, Jiyu Yan, Breanna Brown, Xiaoyang Lin, Ning Shen, Yanhong Wang, Haohan Zhao, Marcia N. Gordon, David Morgan, Qingyu Zhou, Ping Chang and Chuanhai Cao

Int. J. Mol. Sci. 2022, 23(8), 4253; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084253 - 12 Apr 2022

Cited by 4 | Viewed by 2193

Abstract

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aβ1–40 and 1–42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer’s disease-related cognitive performance. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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20 pages, 7826 KiB

Open AccessArticle

Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis

by Sabine Tacke, Rittika Chunder, Verena Schropp, Eduard Urich and Stefanie Kuerten

Int. J. Mol. Sci. 2022, 23(6), 3172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063172 - 15 Mar 2022

Cited by 3 | Viewed by 2772

Abstract

Successful therapy with anti-CD20 monoclonal antibodies (mAbs) has reinforced the key role of B cells in the immunopathology of multiple sclerosis (MS). This study aimed to determine the effects of a novel class of anti-CD20 mAbs on vascular and extravascular central nervous system (CNS)-infiltrating B cells in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male hCD20xhIgR3 mice and wild-type C57BL/6 (B6) mice were immunized with human myelin oligodendrocyte glycoprotein (MOG)_1–125 to induce EAE. While hCD20xhIgR3 mice were injected intravenously with an anti-human CD20 mAb (5 mg/kg) (rituximab (a type I anti-CD20 mAb) or obinutuzumab (a type II anti-CD20 mAb), B6 mice received the anti-mouse CD20 antibody 18B12. Neither mAb affected clinical disease or serum antibody levels. Obinutuzumab and rituximab had an impact on splenic and CNS-infiltrated B cells with slightly differential depletion efficacy. Additionally, obinutuzumab had beneficial effects on spinal cord myelination. B cell depletion rates in the 18B12/B6 model were comparable with those observed in obinutuzumab-treated hCD20xhIgR3 mice. Our results demonstrate the usefulness of anti-CD20 mAbs for the modulation of B cell-driven peripheral immune response and CNS pathology, with type II antibodies potentially being superior to type I in the depletion of tissue-infiltrating B cells. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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26 pages, 6980 KiB

Open AccessArticle

Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice

by Yanhong Wang, Yuzhu Hong, Jiyu Yan, Breanna Brown, Xiaoyang Lin, Xiaolin Zhang, Ning Shen, Minghua Li, Jianfeng Cai, Marcia Gordon, David Morgan, Qingyu Zhou and Chuanhai Cao

Int. J. Mol. Sci. 2022, 23(5), 2757; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052757 - 02 Mar 2022

Cited by 10 | Viewed by 3690

Abstract

Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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22 pages, 3779 KiB

Open AccessArticle

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation

by Matthias Apweiler, Jana Streyczek, Soraya Wilke Saliba, Juan Antonio Collado, Thomas Hurrle, Simone Gräßle, Eduardo Muñoz, Claus Normann, Sabine Hellwig, Stefan Bräse and Bernd L. Fiebich

Int. J. Mol. Sci. 2022, 23(2), 959; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020959 - 16 Jan 2022

Cited by 5 | Viewed by 2271

Abstract

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE₂-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE₂-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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25 pages, 3617 KiB

Open AccessArticle

Murine Esophagus Expresses Glial-Derived Central Nervous System Antigens

by Christopher Kapitza, Rittika Chunder, Anja Scheller, Katherine S. Given, Wendy B. Macklin, Michael Enders, Stefanie Kuerten, Winfried L. Neuhuber and Jürgen Wörl

Int. J. Mol. Sci. 2021, 22(6), 3233; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063233 - 22 Mar 2021

Cited by 7 | Viewed by 2823

Abstract

Multiple sclerosis (MS) has been considered to specifically affect the central nervous system (CNS) for a long time. As autonomic dysfunction including dysphagia can occur as accompanying phenomena in patients, the enteric nervous system has been attracting increasing attention over the past years. The aim of this study was to identify glial and myelin markers as potential target structures for autoimmune processes in the esophagus. RT-PCR analysis revealed glial fibrillary acidic protein (GFAP), proteolipid protein (PLP), and myelin basic protein (MBP) expression, but an absence of myelin oligodendrocyte glycoprotein (MOG) in the murine esophagus. Selected immunohistochemistry for GFAP, PLP, and MBP including transgenic mice with cell-type specific expression of PLP and GFAP supported these results by detection of (1) GFAP, PLP, and MBP in Schwann cells in skeletal muscle and esophagus; (2) GFAP, PLP, but no MBP in perisynaptic Schwann cells of skeletal and esophageal motor endplates; (3) GFAP and PLP, but no MBP in glial cells surrounding esophageal myenteric neurons; and (4) PLP, but no GFAP and MBP in enteric glial cells forming a network in the esophagus. Our results pave the way for further investigations regarding the involvement of esophageal glial cells in the pathogenesis of dysphagia in MS. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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Review

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27 pages, 2286 KiB

Open AccessReview

Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

by Priyanka Rawat, Ujala Sehar, Jasbir Bisht, Ashley Selman, John Culberson and P. Hemachandra Reddy

Int. J. Mol. Sci. 2022, 23(21), 12841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112841 - 25 Oct 2022

Cited by 57 | Viewed by 8661

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer’s brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, Alzheimer’s disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington’s disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies. Full article

(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases 2.0)

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