Alzheimer's disease (AD) is the most common form of dementia, and no therapies currently exist that prevent or slow its progression. Lactate has recently emerged as both an energy substrate and a signaling molecule required for memory formation, acting in part through a novel epigenetic mechanism termed histone lactylation. Here, we used matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) imaging mass spectrometry and immunofluorescence microscopy to spatially map lactate, glutamate, pyruvate, and citrate levels, alongside histone lactylation, in the brains of wild type and AD transgenic mice at 6 and 18 months of age. Lactate and glutamate were highest in young animals and declined with age, while pyruvate showed the inverse pattern. These shifts were most pronounced in females, and pyruvate-to-lactate and pyruvate-to-citrate ratios suggested a progressive, region-specific shift from glycolytic to oxidative metabolism. Sex was a dominant determinant of cerebral metabolite distribution: females maintained consistently higher lactate and glutamate than males at both ages, indicating a sex-specific metabolic phenotype that persists across physiological aging. Elevated lactate levels were paralleled by increased histone lactylation in aged females, particularly within the cortex and CA2/CA3 hippocampal subregion, and in transgenic females lactylation was enriched in putative microglia near amyloid plaques. Lactate and histone lactylation were positively correlated in wild type mice, consistent with a lactate-driven epigenetic mechanism possibly in microglia, but this relationship was weakened or absent in transgenic mice despite elevated plaque-adjacent lactylation, suggesting amyloid pathology decouples metabolic state from epigenetic regulation. These findings identify sex as a major, underappreciated variable shaping brain metabolic-epigenetic coupling during aging and amyloid stress. Together, these results implicate sex-specific lactate metabolism and lactylation signaling as potential contributors to differential AD vulnerability, and underscore the need to incorporate sex as a biological variable in future studies of metabolic-epigenetic mechanisms and therapeutic targeting in AD.
Grahovac-Nemeth, S., Jurcic, K., Courchesne, M., Nygard, K., Callahan, G., Frame, A. K., Khazaee, R., Wang, W., Ganeshalingam, M., Thomas, R., Whitehead, S. N., Cumming, R. C.
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