Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation

The NLRP3 Inflammasome and Pro-Inflammatory Cytokines in Alzheimer's Disease: Molecular Mechanisms, Neuroimmune Crosstalk, Biomarkers, and Emerging Therapeutic Perspectives

The molecular mechanisms underlying NLRP3 inflammasome activation in Alzheimer’s disease, its interaction with pro-inflammatory cytokine networks, and the emerging role of inflammasome-related biomarkers in disease characterization are examined.

Vitamin B12-mediated microglial immunometabolic reprogramming: A novel mechanistic insight into diabetes-associated cognitive impairment.

Diabetes-associated cognitive impairment (DCI) is an increasingly recognized neurological complication of type 2 diabetes mellitus characterized by chronic neuroinflammation and microglial immunometabolic dysregulation. Vitamin B12 (VB12) deficiency, which is highly prevalent in patients with diabetes, has been strongly associated with cognitive decline, hippocampal atrophy, and white matter injury. Emerging evidence suggests that VB12 plays a critical role in maintaining one‑carbon metabolism, mitochondrial function, and redox homeostasis. Mechanistically, VB12 deficiency promotes homocysteine accumulation, disrupts the S-adenosylmethionine/S-adenosylhomocysteine balance, impairs mitochondrial oxidative phosphorylation, and enhances oxidative stress, thereby driving pro-inflammatory microglial activation and sustained neuroinflammation. In addition, gut microbiota dysbiosis, particularly reduced abundance of Akkermansia muciniphila and other VB12-producing bacteria, may further impair VB12 bioavailability and aggravate neuroinflammation through the gut-brain axis. This review summarizes current evidence linking VB12 deficiency to microglial immunometabolic remodeling in DCI and discusses the therapeutic potential of targeting VB12 metabolism and gut microbial ecology for preventing diabetes-related cognitive decline.

Phosphatidylethanolamine-mediated metabolic membrane remodeling in obesity-associated Alzheimer’s disease: mechanisms, neuroimmune crosstalk, and therapeutic potential

Targeting the NLRP3 Inflammasome in Alzheimer's Disease: Mechanistic Insights and Therapeutic Advances.

Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K+ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.

The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer’s and Parkinson’s diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage—inflammatory activation—autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.

Microglial immunometabolism in Alzheimer's disease: A stage-resolved trajectory from adaptive remodeling to the metabolic paradox.

Microglia are central regulators of the cellular phase of Alzheimer's disease (AD). Under chronic exposure to amyloid-β, pathological tau, and aging-associated bioenergetic decline, these cells undergo immunometabolic remodeling that may initially be adaptive. As stress persists, this remodeling can become maladaptive, marked by disordered glycolysis, disturbed lipid handling, mitochondrial dysfunction, and compensatory failure. In this review, we organize these changes as a stage-dependent trajectory from adaptive remodeling to functional decompensation. We introduce the "metabolic paradox" as an operational descriptor: a concurrent, same-cell mismatch between increased substrate uptake or inflammatory activation and declining bioenergetic efficiency and homeostatic function. Along this trajectory we examine neurovascular energy bottlenecks, substrate redistribution, triggering receptor expressed on myeloid cells 2 (TREM2)/apolipoprotein E (APOE)-dependent lipid homeostasis, mitochondrial and proteostatic collapse, and their links to persistent neuroinflammation, defective phagocytosis, aberrant synaptic pruning, and senescence-like dysfunction. We synthesize prior primary findings and stratify each major claim by evidentiary strength, avoiding the overinterpretation of model-specific results as patient-level mechanisms. Finally, we frame immunoprevention as mechanism-based, early-stage metabolic intervention to preserve homeostatic microglial function, a strategy whose clinical benefit remains a hypothesis requiring prospective testing.