Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques.

Area of Science:

• Neuroscience
• Immunology
• Metabolic Disorders

Background:

• Hypercholesterolemia is linked to Alzheimer's disease (AD), but its precise impact on AD pathology, microglial function, and amyloid-beta (Aβ) dynamics is not fully understood.
• Investigating the interplay between genetic predisposition, diet, and AD progression is crucial for understanding disease mechanisms.

Purpose of the Study:

• To elucidate the mechanistic link between hypercholesterolemia and Alzheimer's disease (AD) pathology.
• To examine the effects of hypercholesterolemia on microglial function and amyloid-beta (Aβ) dynamics in an AD mouse model.

Main Methods:

• Utilized APP ^NL-G-F (AK) and APP ^NL-G-F;LDLR ^-/- (AL ^KO) mouse models under control and Western diets (WD) to induce hypercholesterolemia.
• Performed RNA sequencing and lipidomic profiling on microglia to assess functional and metabolic changes.
• Conducted behavioral analyses to evaluate cognitive performance and anxiety-like behaviors.

Main Results:

• Hypercholesterolemia suppressed microglial clustering and activation around Aβ plaques, reducing plaque compactness.
• RNA sequencing revealed impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation.
• Lipidomic analysis showed a pro-inflammatory microglial lipidome, and behavioral tests indicated impaired cognition and increased anxiety.

Conclusions:

• Hypercholesterolemia exacerbates AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function.
• Pharmacological management of hypercholesterolemia may represent a therapeutic strategy to slow AD progression.