Rho-kinase ROCK inhibitors reduce oligomeric tau protein.
Alzheimer Disease
/ drug therapy
Animals
Autophagy
/ drug effects
Cell Line, Tumor
Cells, Cultured
Disease Models, Animal
Enzyme Inhibitors
/ pharmacology
Humans
Mice
Neurofibrillary Tangles
/ metabolism
Phosphorylation
/ drug effects
Proteasome Endopeptidase Complex
/ metabolism
Proteolysis
/ drug effects
Quinolines
/ pharmacology
Signal Transduction
/ drug effects
Tauopathies
/ drug therapy
rho-Associated Kinases
/ antagonists & inhibitors
tau Proteins
/ metabolism
Alzheimer's disease
Phosphorylation
ROCK inhibitor
Tau oligomer
Tau protein
Journal
Neurobiology of aging
ISSN: 1558-1497
Titre abrégé: Neurobiol Aging
Pays: United States
ID NLM: 8100437
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
17
04
2019
revised:
09
12
2019
accepted:
10
12
2019
pubmed:
27
1
2020
medline:
24
9
2020
entrez:
27
1
2020
Statut:
ppublish
Résumé
Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.
Identifiants
pubmed: 31982202
pii: S0197-4580(19)30437-3
doi: 10.1016/j.neurobiolaging.2019.12.009
pmc: PMC7183001
mid: NIHMS1573226
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Quinolines
0
tau Proteins
0
rho-Associated Kinases
EC 2.7.11.1
Proteasome Endopeptidase Complex
EC 3.4.25.1
pitavastatin
M5681Q5F9P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
41-54Subventions
Organisme : NIA NIH HHS
ID : R01 AG044372
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS082730
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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