Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
23
07
2019
accepted:
02
07
2020
pubmed:
12
8
2020
medline:
1
12
2020
entrez:
12
8
2020
Statut:
ppublish
Résumé
Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer's disease and frontotemporal dementia, diseases characterized by the accumulation of hyperphosphorylated forms of the microtubule-associated protein tau. However, it is unclear whether tau contributes to these neurovascular alterations independent of neurodegeneration. We report that mice expressing mutated tau exhibit a selective suppression of neural activity-induced cerebral blood flow increases that precedes tau pathology and cognitive impairment. This dysfunction is attributable to a reduced vasodilatation of intracerebral arterioles and is reversible by reducing tau production. Mechanistically, the failure of neurovascular coupling involves a tau-induced dissociation of neuronal nitric oxide synthase (nNOS) from postsynaptic density 95 (PSD95) and a reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. These data identify glutamatergic signaling dysfunction and nitric oxide deficiency as yet-undescribed early manifestations of tau pathobiology, independent of neurodegeneration, and provide a mechanism for the neurovascular alterations observed in the preclinical stages of tauopathies.
Identifiants
pubmed: 32778793
doi: 10.1038/s41593-020-0686-7
pii: 10.1038/s41593-020-0686-7
pmc: PMC7896353
mid: NIHMS1609145
doi:
Substances chimiques
Disks Large Homolog 4 Protein
0
Dlg4 protein, mouse
0
tau Proteins
0
Nitric Oxide Synthase Type I
EC 1.14.13.39
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
1079-1089Subventions
Organisme : NINDS NIH HHS
ID : R01 NS037853
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097805
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG019391
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095441
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109588
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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