Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques

Hypercholesterolemia is a recognized comorbidity of Alzheimer's disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APP^NL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APP^NL-G-F;LDLR^−/− (AL^KO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a control diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.