D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner

Background Oxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer’s disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. Objective To 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 mouse models. Methods Male and female APP/PS1 and APP NL-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 using biochemical and histological analyses. Results D-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APP NL-F mice. APP NL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APP NL-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, assessed by malondialdehyde, was reduced only in female APP NL-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 (pgWAT) IL-6 expression in female APP NL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APP NL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. Conclusion Short-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APP NL-F mice.