Fig. 1.

Effect of microglia on Aβ and tau pathology in Alzheimer’s disease. Microglia phagocytose Aβ and tau, limit propagation of Aβ and tau pathology. Under pathological conditions, microglia could also accelerate Aβ and tau spreading and lead to neurodegeneration. a TREM2-dependent DAM limits tau seeding and spreading around plaques. b Reactive microglia drive tau spreading and toxicity by promoting neuroinflammation, such as activating NLRP3 inflammasome or inducing NF-_kB signaling. Microglial autophagy deficiency leads to dysregulation of lipid metabolism, thus increasing intraneuronal tau pathology and its spreading. MGnD microglia, which is common in neurodegeneration, hypersecrete EVs containing pTau, accelerates tau propagation. c Microglia increase their expression of IL-3Rα after recognition of Aβ deposits. Astrocyte-derived IL-3 binds to the upregulated IL-3Rα in microglia, enhancing microglial migration toward Aβ deposits, and the clearance of Aβ aggregates. d TREM2 promotes the conversion of microglia to the DAM phenotype, and BACE-1 inhibition in microglia facilitates the microglia phenotype transition from homeostatic to DAM-1 signature. DAM and DAM-1 phenotypes enhance amyloid clearance. LC3-associated endocytosis (LANDO) in microglia facilitates Aβ receptor recycling, increases Aβ surface receptors, and thus promotes Aβ clearance. In contrast, the microglia with enhanced aerobic glycolysis, and NgR expression on microglia increased with aging inhibit the phagocytosis and clearance of Aβ. e Microglia facilitate Aβ spreading. Aβ induces immune system activation and the formation and release of ASC specks. After being released from microglia, ASC specks bind to and promote the cross-seeding of Aβ, leading to amyloid seeding and spreading. Created with https://BioRender.com