β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage

Accumulation of beta-amyloid (A beta) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of AD patients and mice models of AD suggested that cholesterol homeostasis is altered in neurons that accumulate A beta. Here we directly investigated the role of intracellular oligomeric A beta(42) (oA beta(42)) in neuronal cholesterol homeostasis. We report that oA beta(42) induces cholesterol sequestration without increasing cellular cholesterol mass. Several features of AD, such as endosomal abnormalities, brain accumulation of A beta and neurofibrillary tangles, and influence of apolipoprotein E genotype, are also present in Niemann-Pick type C, a disease characterized by impairment of intracellular cholesterol trafficking. These common features and data presented here suggest that a pathological mechanism involving abnormal cholesterol trafficking could take place in AD. Cholesterol sequestration in A beta-treated neurons results from impairment of intracellular cholesterol trafficking secondary to inhibition of protein prenylation. oA beta(42) reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism ofoA beta(42)-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oA beta(42)-treated neurons recovers normal protein prenylation, reduces cholesterol sequestration, and prevents A beta-induced neurotoxicity. Significant to AD, reduced levels of protein prenylation are present in the cerebral cortex of the TgCRND8 mouse model. In conclusion, we demonstrate a significant inhibitory effect of A beta on protein prenylation and identify SREBP-2 as a target of oA beta(42), directly linking A beta to cholesterol homeostasis impairment.