Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

---

Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Abstract Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer’s disease. Efficient clearance has been proven in clinical trials testing anti-Aβ antibodies, with the impact on endpoints correlating extent removal. However, treatment is associated adverse side-effects, such as oedema haemorrhages, which are potentially linked induced immune response. To improve safety profile these molecules, it imperative understand consequences antibody cell function. Here, we investigated effects long-term chronic microglial response APP-SAA triple knock-in mouse model. Mice were treated weekly from 4-8 months age. Long-term results a robust dose-dependent removal pathology, higher efficiency for removing diffuse over dense-core plaques. Analysis CSF proteome indicates reduction markers neurodegeneration including Tau α-Synuclein, well related proteins. Bulk RNA-seq revealed decrease brain-wide disease-associated (DAM) glycolytic gene expression, supported by parallel glucose uptake protein levels Triggering receptor myeloid cells 2 (Trem2) protein, major involved DAM activation microglia. In contrast, around remaining plaques remains high regardless dose. addition, microglia surrounding display increase clustering selective antigen presenting signalling These findings demonstrate that mediated Aβ leads dose dependent neurodegeneration, while at residual combined phenotype suggests continued Figure Graphical abstract: Schematic overview mice created BioRender.com

Language: Английский

---

Microglial and TREM2 dialogues in the developing brain

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

---

Microglia transcriptional states and their functional significance: Context drives diversity

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

---