From Mechanisms to Medicine: Astrocyte Dysfunction in Stress-Related Neuroinflammation and Alzheimer's Disease

Chronic stress is increasingly acknowledged as a pivotal precipitating factor in the pathogenesis of neuropsychiatric and neurodegenerative disorders, notably including depression and Alzheimer's disease (AD). Astrocytes, which constitute the predominant population of glial cells involved in the maintenance of synaptic homeostasis, the recycling of neurotransmitters, and the provision of metabolic support, display a pronounced susceptibility to sustained exposure to stress. The deleterious effects of astrocytic dysfunction instigate a series of neuroinflammatory and synaptic modifications that undermine both cognitive and emotional resilience. This review articulates the mechanistic interactions between stress-induced astrocyte dysfunction, neuroinflammatory signaling, and compromised neuroplasticity, underscoring the converging pathways that are implicated in both depression and AD. A thorough synthesis of the literature from 2020 to 2025 was conducted utilizing databases such as PubMed, Scopus, and Web of Science, with an emphasis on molecular, in vitro, in vivo, and translational studies that examine the modulation of astrocytic function under conditions of chronic stress and its pertinence to depression and AD. The chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis precipitates morphological alterations, diminished expression of glutamate transporters (GLT-1/EAAT2), disrupted brain-derived neurotrophic factor (BDNF) signaling, and an augmented release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) from astrocytes. These biochemical alterations exacerbate excitotoxicity, disturb monoaminergic and glutamatergic neurotransmission, and hasten synaptic degeneration. In the context of depression, this phenomenon is manifested as impaired mood regulation and a decline in neurogenesis. In AD, it synergistically interacts with amyloid-beta and tau pathologies to facilitate progressive cognitive impairment. Both conditions exhibit a common feature of diminished neurosignaling plasticity, which limits the brain's capacity for adaptation and repair. Astrocyte dysfunction constitutes a central mechanistic nexus wherein chronic stress, neuroinflammation, and synaptic pathology intersect to promote the progression of depression and AD. The targeting of astrocytic health via the modulation of reactive astrocyte phenotypes, the restoration of glutamate homeostasis, and the enhancement of neurotrophic signaling emerges as a promising therapeutic avenue for alleviating stress-related neurodegeneration and mood disorders.