Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease

Astrocyte reactivity is a primary nexus for the cerebrovascular and neuronal pathologies that arise with AD. The major functional phenotypes associated with astrocyte reactivity include neuroinflammation, impaired glutamate/potassium homeostasis, hypometabolism, and loss of endfoot integrity, all of which are extensively intertwined. Neuroinflammatory pathways directly affect nearby glial cells, neurons, and neurovascular elements (orange arrows). Glutamate and potassium dysregulation directly affect astrocyte metabolism, synapse function, and vascular endothelial cells (green arrows). Breakdown of astrocyte endfoot processes, lead to the loss of BBB integrity, Ca2+ dysregulation, and impaired glymphatic clearance. Impaired astrocyte metabolism directly erodes neuronal viability and glymphatic clearance of interstitial toxins, including Aβ (blue arrows), which, in turn, create an inhospitable environment for neurons marked by elevated neuroinflammation and excitotoxicity (purple arrow).