Ketone monoester alleviates cognitive impairment in a transgenic mouse model of Alzheimer’s disease through innate immunological IFITM3 pathway

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by irreversible cognitive decline and cerebral dysfunction, remains a major global health challenge due to elusive pathogenesis and the lack of disease-modifying therapies. Growing evidence underscores the neuroprotective potential of ketone bodies, particularly β-hydroxybutyrate (β-HB), owing to their diverse biological roles in mitigating AD-related pathology. Recent advances also implicate innate immunity in AD progression, identifying interferon-induced transmembrane protein 3 (IFITM3) as a pivotal regulator of amyloid-β (Aβ) formation. In this study, BD-AcAc2 was administered to induce exogenous ketosis in APP/PS1 transgenic mice, and Aβ-stimulated astrocytes were employed to explore the mechanistic role of β-HB as a nutritional intervention. Our findings demonstrate that β-HB significantly enhanced cognitive performance and reduced hippocampal amyloid plaque burden in APP/PS1 mice, likely through modulation of the IFITM3 pathway. Furthermore, β-HB attenuated Aβ-induced IFITM3 activation, decreased reactive oxygen species (ROS) levels, and downregulated pro-inflammatory cytokine expression in astrocytes. Collectively, these results establish β-HB as a neuroprotective agent that acts through IFITM3-mediated mechanisms, providing novel insights into therapeutic strategies targeting metabolic-immune interactions in AD.