Roles of Microglia and Astrocytes in Neuroinflammation of Alzheimer's Disease: From Mechanisms to Therapeutics

Abstract

Alzheimer's disease (AD) is one of the most common types of neurodegenerative diseases. Its pathogenesis involves the interaction of multiple factors, including β-amyloid deposition, excessive tau protein phosphorylation, neuroinflammation, and synaptic dysfunction. Among these, neuroinflammation is widely recognized as a key factor driving the onset and progression of AD. As the two main types of glial cells in the central nervous system, microglia and astrocytes play central roles in the regulation of neuroinflammation. This paper systematically reviews the structural characteristics and functional states of microglia and astrocytes in AD-related neuroinflammation, as well as their interactions with Aβ and tau pathologies. Both types of glial cells exhibit a bidirectional transition from a protective to a damaging phenotype. In the early stage, they exert neuroprotective effects by phagocytosing and clearing abnormal proteins and releasing neurotrophic factors. Under sustained inflammatory stimulation, both gradually shift to a pro-inflammatory activated state, releasing large amounts of inflammatory factors, disrupting the blood-brain barrier and glymphatic system, and abnormally phagocytosing synaptic structures, forming a vicious cycle in which pathological protein deposition and excessive glial cell activation mutually exacerbate each other. More importantly, the two types of glial cells interact through various pathways such as cytokines, complement pathways, and signaling molecules, jointly amplifying the inflammatory cascade. This paper also summarizes therapeutic strategies for drugs targeting these two glial cells, including cholinesterase inhibitors, NMDA receptor antagonists, non-steroidal anti-inflammatory drugs, and biological agents targeting Aβ and tau proteins. In conclusion, functional abnormalities and interactive disorders of microglia and astrocytes are the core driving factors of AD neuroinflammation. An in-depth understanding of the molecular mechanisms underlying their interaction will provide a new breakthrough for shifting AD treatment from symptomatic management to etiological eradication.