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Neuronal membrane cholesterol loss enhances amyloid peptide generation

¹ Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043 Orbassano (TO), Italy
² Center for Human Genetics, Catholic University of Leuven and Flanders Interuniversitary Institute for Biotechnology, 3000 Leuven, Belgium
³ Unité INSERM 422, Lille, France
⁴ Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM195AW, England, UK

Correspondence to Carlos G. Dotti: carlos.dotti{at}unito.it; or Bart De Strooper: Bart.Destrooper{at}med.kuleuven.ac.be

Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its ß-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1–APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.

Abbreviations used in this paper: Aß, amyloid peptide; AD, Alzheimer's disease; ß-CTF, ß-COOH-terminal fragment; CNS, central nervous system; DRM, detergent-resistant membrane; MCD, methyl-ß-cyclodextrin; SFV-APP, Semliki Forest virus/human APP.

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