This study applied MALDI-TOF imaging mass spectrometry together with immunofluorescence microscopy to create spatial maps of brain energy metabolites and a related epigenetic mark in a mouse model relevant to Alzheimer’s disease (AD). The metabolites measured were lactate, glutamate, pyruvate, and citrate. Histone lactylation was assessed as an epigenetic readout potentially linked to lactate signaling. Analyses compared wild type and AD transgenic mice at two time points: 6 months and 18 months of age.
Across the cohort, lactate and glutamate concentrations were highest in the younger (6-month) animals and declined by 18 months. Pyruvate displayed the opposite trajectory, increasing with age. Citrate was measured alongside these metabolites to inform interpretations of central carbon metabolism. Computed ratios such as pyruvate-to-lactate and pyruvate-to-citrate suggested a progressive, region-specific transition from glycolytic toward more oxidative metabolic profiles with aging and/or amyloid-related stress.
Sex emerged as a dominant determinant of metabolite distribution. Females retained consistently higher levels of lactate and glutamate than males at both ages assessed, indicating a sex-specific metabolic phenotype that persists across physiological aging. The metabolic shifts with age (declining lactate and glutamate; increasing pyruvate) were most pronounced in females, highlighting greater age-related remodeling of cerebral energy metabolism in female mice within this model.
Regional analyses indicated that metabolic and epigenetic changes were not uniform across the brain. Elevated lactate and increased histone lactylation in aged females were especially evident in the cortex and within the CA2/CA3 subregion of the hippocampus. Ratios pointing to a shift from glycolysis to oxidative metabolism varied by brain region, suggesting localized metabolic reprogramming during aging and in response to amyloid pathology.
Histone lactylation increased in aged female mice in parallel with elevated lactate levels, supporting a linkage between metabolic substrate availability and epigenetic modification. In transgenic (AD model) females, histone lactylation was enriched in putative microglia located near amyloid plaques, indicating a localized epigenetic response in plaque-adjacent immune cells. Thus, histone lactylation showed both age- and sex-dependent patterns and distinct cellular localization in the presence of amyloid pathology.
In wild type animals, lactate levels and histone lactylation were positively correlated, consistent with a model in which lactate acts as a substrate or signal driving histone lactylation. In transgenic mice, however, this relationship was weakened or absent despite observations of elevated plaque-adjacent lactylation. The authors interpret this dissociation as evidence that amyloid pathology can decouple the usual metabolic–epigenetic coupling, such that local lactylation near plaques does not reflect the same global metabolic-epigenetic relationship seen in non-transgenic animals.
The findings identify sex as a major and underappreciated variable shaping brain metabolic–epigenetic coupling during aging and amyloid stress. Sex-specific differences in lactate metabolism and lactylation signaling are implicated as potential contributors to differential vulnerability in AD. The authors emphasize the importance of incorporating sex as a biological variable in future studies that investigate metabolic–epigenetic mechanisms and that seek therapeutic targets in AD. These results suggest that therapies or interventions that influence lactate metabolism or histone lactylation may have sex-dependent effects, although efficacy or translational implications were not directly tested in this report.
The study employed spatial metabolite mapping using MALDI-TOF imaging mass spectrometry together with immunofluorescence microscopy. Analyses compared wild type and AD transgenic mice at two ages (6 and 18 months). Measured metabolites were lactate, glutamate, pyruvate, and citrate; histone lactylation was assessed to probe epigenetic coupling to metabolic state. Regional observations highlighted cortex and CA2/CA3 hippocampal subregions, and cellular localization implicated putative microglia in plaque-adjacent lactylation in transgenic females. Specific experimental parameters, quantification thresholds, sample sizes, and statistical details were not reported in the source summary and therefore are not described here.
Conclusion
Using spatially resolved metabolomics and immunofluorescence, the authors report age- and sex-dependent reprogramming of brain energy metabolism and associated histone lactylation in a mouse model of AD pathology. Females showed higher cerebral lactate and glutamate across ages and more pronounced age-related metabolic shifts. Histone lactylation increased with elevated lactate in aged females, and in transgenic females was concentrated in putative microglia near amyloid plaques. The weakened lactate–lactylation correlation in transgenic mice suggests amyloid pathology can disrupt normal metabolic–epigenetic coupling. The study underscores the need to include sex as a biological variable when investigating metabolic and epigenetic mechanisms in AD.