D-methionine improves spatial navigation and attenuates oxidative stress and amyloid pathology in a sex-specific manner

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches.ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD models.MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic, and inflammatory markers, and hippocampal microglial phenotypes were evaluated.ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved Morris water maze learning. Amyloid pathology was region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ)₄₂ in male APP/PS1 mice. Lipid peroxidation was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met decreased microglial activation, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial markers and increased Axl expression.ConclusionsShort-term D-Met acts as a metabolic and redox modulator with amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.