Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration
- 10 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 23 (9), 1079-1089
- https://doi.org/10.1038/s41593-020-0686-7
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (097805, 109588, 37853)
- Japan Heart Foundation/Bayer Research Grant Abroad (YH), The Uehara Memorial Foundation Research Fellowship (YH), Japan Society for the Promotion of Science Overseas Research Fellowship
- American Heart Association (20POST35120063)
This publication has 69 references indexed in Scilit:
- The role of nitric oxide in pre-synaptic plasticity and homeostasisFrontiers in Cellular Neuroscience, 2013
- Presymptomatic cerebral blood flow changes inCHMP2Bmutation carriers of familial frontotemporal dementia (FTD-3), measured with MRIBMJ Open, 2012
- Modulation of Heme/Substrate Binding Cleft of Neuronal Nitric-oxide Synthase (nNOS) Regulates Binding of Hsp90 and Hsp70 Proteins and nNOS UbiquitinationOnline Journal of Public Health Informatics, 2012
- Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-βProceedings of the National Academy of Sciences of the United States of America, 2011
- Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of NeurodegenerationNeuron, 2010
- Chronic Intermittent Hypoxia Induces NMDA Receptor-Dependent Plasticity and Suppresses Nitric Oxide Signaling in the Mouse Hypothalamic Paraventricular NucleusJournal of Neuroscience, 2010
- NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2Journal of Neuroscience, 2009
- Key role of tissue plasminogen activator in neurovascular couplingProceedings of the National Academy of Sciences of the United States of America, 2008
- Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)Journal of Neuroscience, 2005
- Tau Suppression in a Neurodegenerative Mouse Model Improves Memory FunctionScience, 2005