Alzheimer Pathology and Neurovascular Dysfunction

Alzheimer’s disease and related dementias (AD/ADRD) are leading causes of age-related cognitive impairment, currently untreatable. Increasing evidence indicates that functional alterations of the cerebral microcirculation may play a role in the pathogenesis of AD/ADRD by reducing the cerebral blood supply. The health of the brain requires a continuous supply of O2 and nutrients through blood flow, tightly matched to its dynamic and regionally diverse energy needs. Accordingly, neural activity increases blood flow in active brain regions (functional hyperemia). Functional hyperemia depends in large part on the link between NMDA receptor activity and neuronal production of the potent vasodilator nitric oxide (NO), and requires tissue plasminogen activator (tPA) for its full expression. The microtubule associated protein tau is a key pathogenic factor in AD and other ADRD caused by tau mutations (tauopathies), but little is known about its role in the neurovascular dysfunction associated in with AD/ADRD. Studies during the previous funding period have discovered that tau disrupts the link between NMDA receptor activity and NO production and suppresses functional hyperemia. Since, in tauopathies, including AD, neocortical neural networks are hyperactive, the failure of functional hyperemia could be particularly damaging by reducing the brain’s O2 supply in the face of the increased energy demands caused by aberrant network activity. In this renewal application we seek to address this critical issue by elucidating the neural and microvascular bases of the effects of p-tau on neurovascular coupling and on neural network activity, and their impact on brain O2 delivery. To this end, we will test the hypothesis that the neuronal NO deficit induced by p-tau disrupts the microvascular bases of functional hyperemia and leads to neural network hyperactivity, which, in turn, results in a potentially harmful reduction in brain O2. To this end, we will use advanced imaging approaches in awake PS19 mice, a tauopathy model, to test the following hypotheses: (a) The NO deficit induced by p-tau leads to aberrant neural network activity and disrupts the orderly microvascular events underlying functional hyperemia; (b) The combination of aberrant neural network activity and impaired functional hyperemia leads to reduced brain O2 availability, rescuable by O2 supplementation; (c) Restoring neuronal NO production with tPA counteracts neurovascular dysfunction, network hyperactivity, and reduced brain O2, and ameliorates tau pathology and cognitive dysfunction. These studies will unveil a new aspect of p-tau pathobiology related to a deleterious mismatch between O2 supply and demands, and may provide the mechanistic bases for new therapies for AD and other tauopathies.