Environmental Pollutants and Neuroinflammation in Alzheimer’s Disease Progression

Microglia-mediated neuroinflammation in Alzheimer’s disease: mechanisms and emerging therapeutic targets

A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.

The Role of Neuroinflammation in Alzheimer's Disease: Molecular Mechanisms and Emerging Therapeutic Approaches

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-beta (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuronal loss. Increasing evidence indicates that neuroinflammation is not merely a secondary consequence of neurodegeneration but an important component of AD pathogenesis. This review examines the molecular and cellular mechanisms through which neuroinflammation contributes to the progression of AD, with particular emphasis on microglial activation, TREM2 and soluble TREM2 (sTREM2) signaling, NLRP3 inflammasome activation, astrocyte–microglia interactions, and blood–brain barrier dysfunction. The review further evaluates emerging therapeutic strategies aimed at modulating these pathways, including NLRP3 inhibition, TREM2/sTREM2-targeted approaches, restoration of glial homeostasis, cytokine modulation, and pro-resolving strategies. Current evidence suggests that inflammatory responses may exert both protective and detrimental effects depending on disease stage, duration, and cellular context. Consequently, broad suppression of neuroinflammation may be insufficient and potentially counterproductive. Future therapeutic development may benefit from precision immunomodulation guided by disease-stage-specific biomarkers and molecular profiling. Understanding the complex interactions between neuroinflammation, pathological protein accumulation, glial dysfunction, and neurovascular abnormalities may therefore provide new opportunities for developing disease-modifying approaches to Alzheimer’s disease.

Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease

The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.

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

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.

Targeting cytokine-driven neuroinflammation in Alzheimer's disease: mechanistic insights and pharmacological strategies.

Neuroinflammation and vascular pathology in Alzheimer's Disease: The NRF2/HO-1 axis as a modulator of microglial phenotypes.

Alzheimer's disease (AD) frequently co-occurs with vascular pathology, and this overlap is increasingly recognized as a major driver of cognitive decline in mixed dementia and vascular cognitive impairment and dementia (VCID). Disruption of the neurovascular unit (NVU) creates a perivascular microenvironment rich in inflammatory and oxidative cues that can instruct microglial state transitions. In this review, we argue that perivascular microglia represent a key "decision hub" at the neurovascular interface, where shifts from homeostatic surveillance toward disease-associated microglia (DAM) programs influence both amyloid handling and the amplification of neuroinflammation. We propose that the NRF2/HO-1 axis functions as a context-sensitive phenotype-control module in these niches: NRF2 integrates oxidative/electrophilic stress through KEAP1 and signaling-dependent regulation through the GSK-3/β-TrCP pathway, thereby shaping transcriptional programs that govern inflammatory tone, redox balance, iron handling, and phagocytic competence. Within this network, HO-1 emerges as a key effector because its metabolites, carbon monoxide, bile pigments, and iron-ferritin responses, can modulate innate immune signaling and, potentially, paracrine communication across NVU cell types. We synthesize evidence linking NVU dysfunction to perivascular microglial activation and discuss how NRF2/HO-1 engagement may remain compensatory in early or acute settings yet become maladaptive under chronic stress or prolonged HO-1 activity. Finally, we outline therapeutic implications of targeting NRF2/HO-1 to reprogram perivascular microglia toward protective DAM functions, emphasizing target engagement, timing, dose, and cell-type specificity as critical determinants of translational success.