Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.

BACKGROUND

Alzheimer's disease (AD) is characterized by chronic neuroinflammation alongside amyloid-beta plaque and phosphorylated tau (p-Tau) tangle accumulation. Microglia, as resident immune cells, undergo glycolytic reprogramming that may exacerbate inflammation and impede toxic protein clearance. Specifically, the glycolytic enzyme pyruvate kinase M2 (PKM2) drives proinflammatory microglial phenotypes linked to neurodegeneration. This study investigates how PKM2-mediated microglial glycolytic reprogramming and inflammatory responses alongside Aβ/p-Tau clearance in human AD brains.

METHODS AND

RESULTS

Hippocampal-entorhinal cortex (HP-EC) tissues from 8 AD patients and 8 matched controls underwent multiplex immunohistochemistry and high-resolution spatial analysis. PKM2+Iba1+ microglia density significantly increased in AD versus controls (p < 0.001), predominantly displaying a disease-associated microglial (HAM-like) phenotype (ABCA7+) with concurrent lipid-droplet accumulation (PLIN3+; LDAM phenotype). Spatially, glycolytic PKM2+Iba1+ microglia accumulated near Aβ plaques, p-Tau tangles, and cerebral vasculature. Notably, their distribution around plaques/tau showed anomalous increasing density with distance (p < 0.001), suggesting impaired chemotaxis. Perivascular localization lacked clear chemotactic gradients. Functionally, overall phagocytic activity (CD68+) decreased significantly in AD (p = 0.001), primarily attributed to PKM2- subsets, whereas PKM2+Iba1+ microglia exhibited pronounced phagocytic exhaustion (PLIN2+; p < 0.001), consistent around both Aβ and p-Tau lesions (all p < 0.001).

CONCLUSION

Our study establishes that microglial glycolytic reprogramming via PKM2 promotes a proinflammatory HAM-like phenotype, phagocytic exhaustion, and peri-pathological accumulation with aggregates and cerebral vessels. Targeting glycolytic pathways represents a viable therapeutic strategy for alleviating microglial dysfunction and neuroinflammation in AD.