Role of Reactive Astrocytes in Alzheimer’s Disease

Abstract

Astrocytes respond to any pathological stimulus to the central nervous system including in Alzheimer’s disease (AD). They undergo dramatic remodeling at the molecular, cellular, and functional levels to constitute a heterogeneous population across disease stages that are collectively termed as reactive astrocytes. “Astrocyte reactivity” or “reactive astrogliosis” encompasses multiple distinct states astrocytes adopt across the disease stages. For several decades this phenomenon has been considered a nonspecific reaction to pathological insults without any disease-inducing mechanisms and with no therapeutic value. Recent studies have contrarily underscored the specific roles of astrocytes in disease pathogenesis. With the advent of single-cell and single-nucleus transcriptomics, numerous disease-modifying functions of reactive astrocytes are revealed. Diverse subtypes of reactive astrocytes are currently the major focus of AD research. Previously astrocytes were thought to contribute towards neuronal degeneration by releasing pro-inflammatory mediators in AD. Present evidences indicate that reactive astrocytes also play a pivotal role in neuroprotection, plausibly at the prodromal AD stages by secreting anti-inflammatory molecules, clearing Aβ and limiting neuroinflammation in the CNS. In this chapter we attempt to review the extensive yet subtle functional diversities in reactive astrocytes in AD with respect to metabolic alterations, neuroinflammation, Aβ production and clearance, tau pathology, synaptic plasticity, neurotransmitter recycling, and their impact on neuronal health. We further highlight their contribution in identifying early-stage AD biomarkers. Thus, reactive astrocytes may represent an attractive therapeutic target in halting AD progression, its prevention, or in cure.