Abstract Body

The mechanisms of the cognitive dysfunction caused by vascular factors (vascular cognitive impairment) or neurodegeneration (Alzheimer’s disease, AD) have traditionally been considered distinct, but there is increasing evidence that alterations in cerebral blood vessels play a role both in vascular and neurodegenerative dementias. Indeed, amyloid-beta and tau, major pathogenic factors in AD, have profound cerebrovascular effects. While the cerebrovascular effects of amyloid-beta are well described, recent data indicate that also tau has a profound impact on neurovascular regulation. However, the cerebrovascular dysfunction of tau is mechanistically distinct from that of amyloid beta. In mouse models of tau accumulation tau suppresses the increase in cerebral blood flow produced by neural activity in the somatosensory cortex but, at variance with amyloid-beta, does not impair the ability of cerebral endothelial cells to regulate blood flow. The mechanisms of the effect involve tau-mediated uncoupling of neuronal nitric oxide from NMDA receptors, leading to suppression of glutamate-dependent nitric oxide production, which, in turn, dampens the increase in blood flow produced by synaptic activity. The deficit of neuronal nitric oxide also leads to interneuron network dysfunction and increased neuronal excitability. These finding indicate that both tau and amyloid-beta target the cerebral microvasculature through mechanistically distinct pathogenic processes. The resulting vascular dysfunction may cooperate with amyloid-beta and tau-induced synaptic dysfunction and contribute to cognitive impairment. In the absence of mechanism-based approaches to counteract dementia, targeting cerebrovascular function may offer the opportunity to mitigate the public health impact of one of the most disabling human afflictions.