Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons

TLDR

The amyloid precursor protein (APP) is central to Alzheimer’s disease, undergoing proteolytic processing that releases either amyloidogenic β‑amyloid (Aβ) or a nonamyloidogenic secreted form, with Aβ accumulation in brain lesions thought to drive disease pathology. Reducing hippocampal neuronal cholesterol by 70 % with lovastatin and methyl‑β‑cyclodextrin completely blocks Aβ production while sparing APP sec generation. Aβ inhibition increases its Triton X‑100 solubility, is fully reversible upon cholesterol restoration, and demonstrates that cholesterol is essential for Aβ formation, linking cholesterol to Alzheimer’s disease.

Abstract

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer’s disease. During intracellular transport APP undergoes a series of proteolytic cleavages that lead to the release either of an amyloidogenic fragment called β-amyloid (Aβ) or of a nonamyloidogenic secreted form consisting of the ectodomain of APP (APP sec ). It is Aβ that accumulates in the brain lesions that are thought to cause the disease. By reducing the cellular cholesterol level of living hippocampal neurons by 70% with lovastatin and methyl-β-cyclodextrin, we show that the formation of Aβ is completely inhibited while the generation of APP sec is unperturbed. This inhibition of Aβ formation is accompanied by increased solubility in the detergent Triton X-100 and is fully reversible by the readdition of cholesterol to previously depleted cells. Our results show that cholesterol is required for Aβ formation to occur and imply a link between cholesterol, Aβ, and Alzheimer’s disease.