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Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.

TitleTau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.
Publication TypeJournal Article
Year of Publication2020
AuthorsPark L, Hochrainer K, Hattori Y, Ahn SJi, Anfray A, Wang G, Uekawa K, Seo J, Palfini V, Blanco I, Acosta D, Eliezer D, Zhou P, Anrather J, Iadecola C
JournalNat Neurosci
Volume23
Issue9
Pagination1079-1089
Date Published2020 Sep
ISSN1546-1726
Abstract

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.

DOI10.1038/s41593-020-0686-7
Alternate JournalNat. Neurosci.
PubMed ID32778793
Grant ListR01 NS097805 / NS / NINDS NIH HHS / United States
20POST35120063 / / American Heart Association (American Heart Association, Inc.) /
R37 AG019391 / AG / NIA NIH HHS / United States
109588 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
097805 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
37853 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /