RT Journal Article SR Electronic T1 β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6490 OP 6500 DO 10.1523/JNEUROSCI.0630-12.2012 VO 32 IS 19 A1 Amany Mohamed A1 Lucila Saavedra A1 Alba Di Pardo A1 Simonetta Sipione A1 Elena Posse de Chaves YR 2012 UL http://www.jneurosci.org/content/32/19/6490.abstract AB Accumulation of β-amyloid (Aβ) 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 Aβ. Here we directly investigated the role of intracellular oligomeric Aβ42 (oAβ42) in neuronal cholesterol homeostasis. We report that oAβ42 induces cholesterol sequestration without increasing cellular cholesterol mass. Several features of AD, such as endosomal abnormalities, brain accumulation of Aβ 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 Aβ-treated neurons results from impairment of intracellular cholesterol trafficking secondary to inhibition of protein prenylation. oAβ42 reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism of oAβ42-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ42-treated neurons recovers normal protein prenylation, reduces cholesterol sequestration, and prevents Aβ-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 Aβ on protein prenylation and identify SREBP-2 as a target of oAβ42, directly linking Aβ to cholesterol homeostasis impairment.