| First Author | Park L | Year | 2020 |
| Journal | Nat Neurosci | Volume | 23 |
| Issue | 9 | Pages | 1079-1089 |
| PubMed ID | 32778793 | Mgi Jnum | J:298251 |
| Mgi Id | MGI:6478746 | Doi | 10.1038/s41593-020-0686-7 |
| Citation | Park L, et al. (2020) Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration. Nat Neurosci 23(9):1079-1089 |
| abstractText | 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. |
