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β-amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage.

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