The microtubule-associated protein tau was identified in the neurofibrillary tangles (NFTs) of Alzheimer's disease (AD) more than 30 years ago, and its mutation can directly cause neurodegeneration.As implied by its purification from microtubules, tau was thought to stabilize microtubules and therefore to be of crucial importance in the brain.However, the physiological function of tau is still in debate since there is no detectable deficit in tau-knockout mice until they are 12 months old [1].Recently, Park and colleagues [2] have discovered that tau binds to PSD-95, in competition with neuronal nitric oxidase synthase (nNOS).Decoupling of nNOS from PSD-95 leads to reduced production of nitric oxidase (NO), and therefore impairs cerebrovascular coupling.Suppression of the mutant tau (P301L and P301S) restores NO production and improves cerebrovascular and cognitive functions.These results provide further evidence for the toxic-gain-of-function hypothesis of tau, suggesting that neurovascular coupling may be therapeutically targeted.