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). [Display omitted] •Many Alzheimer’s disease pathophysiological processes are linked through astrocyte reactivity and/or dysfunction.•Astrocyte signaling mechanisms are extensively intertwined and likely impact one another in deleterious ways.•Modifying or resolving reactive astrocyte phenotypes could lead to effective anti-AD treatments. Astrocyte reactivity is a hallmark of neuroinflammation that arises with Alzheimer’s disease (AD) and nearly every other neurodegenerative condition. While astrocytes certainly contribute to classic inflammatory processes (e.g. cytokine release, waste clearance, and tissue repair), newly emerging technologies for measuring and targeting cell specific activities in the brain have uncovered essential roles for astrocytes in synapse function, brain metabolism, neurovascular coupling, and sleep/wake patterns. In this review, we use a holistic approach to incorporate, and expand upon, classic neuroinflammatory concepts to consider how astrocyte dysfunction/reactivity modulates multiple pathological and clinical hallmarks of AD. Our ever-evolving understanding of astrocyte signaling in neurodegeneration is not only revealing new drug targets and treatments for dementia but is suggesting we reimagine AD pathophysiological mechanisms.