Abstract

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 Aβ(42) (oAβ(42)) in neuronal cholesterol homeostasis. We report that oAβ(42) 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. oAβ(42) reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism of oAβ(42)-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ(42)-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 oAβ(42), directly linking Aβ to cholesterol homeostasis impairment.

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Publisher Full Text

Authors

Mohamed A, Saavedra L, Di Pardo A, Sipione S, Posse de Chaves E

Institution

Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.

Source

The Journal of neuroscience : the official journal of the Society for Neuroscience 32:19 2012 May 9 pg 6490-500

MeSH

Amyloid beta-Peptides
Animals
Anticholesteremic Agents
Biological Transport
Cell Death
Cells, Cultured
Cholesterol
Female
Intracellular Space
Male
Mice
Mice, Transgenic
Neurons
Peptide Fragments
Protein Prenylation
Rats
Rats, Sprague-Dawley
Sterol Regulatory Element Binding Protein 2

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22573671