Microvascular dysfunction and aberrant network activity drive reduced brain oxygenation in a mouse tauopathy model.

Tauopathies such as Alzheimer's disease and frontotemporal dementia are leading causes of cognitive impairment, characterized by accumulation of hyperphosphorylated tau, a microtubule-associated protein, in brain. In addition to driving neural network hyperactivity and neuronal damage, tau disrupts neurovascular function, which may further contribute to disease pathogenesis. Using a mouse tauopathy model, we demonstrate that tau causes a profound breakdown of the normally well-coordinated segmental vasodilation induced by neural activity, resulting in dampened and delayed blood-flow increases, heterogeneous capillary perfusion, and frequent capillary stalling. These neurovascular alterations arise in the context of pronounced network hyperactivity and hypersynchrony, which combined with impaired neurovascular coupling, lead to reduced oxygen availability, episodic hypoxia, and disturbed metabolic homeostasis. Collectively, these findings identify reduced brain oxygenation driven by an imbalance between neuronal hyperactivity and diminished oxygen delivery as a previously-unappreciated early pathogenic consequence of tau accumulation and bolster the rationale for therapies to restore cerebral oxygenation.