Elsevier

Neurobiology of Disease

Volume 7, Issue 4, August 2000, Pages 321-331
Neurobiology of Disease

Regular Article
Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model

https://doi.org/10.1006/nbdi.2000.0304Get rights and content

Abstract

Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid β-peptide (Aβ) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Aβ accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Aβ peptides in the CNS. Furthermore, the levels of total Aβ were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPα and increased levels of C-terminal fragments (β-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased β-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Aβ accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD.

References (49)

  • E. McGowan et al.

    Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes

    Neurobiol. Dis.

    (1999)
  • T. Mizuno et al.

    Cholesterol-dependent generation of a unique amyloid beta-protein from apically missorted amyloid precursor protein in MDCK cells

    Biochim. Biophys. Acta

    (1998)
  • W. Nickel et al.

    Protein and lipid sorting between the endoplasmic reticulum and the Golgi complex

    Semin. Cell Dev. Biol.

    (1998)
  • K. Sambamurti et al.

    Glycosylphosphatidylinositol-anchored proteins play an important role in the biogenesis of the Alzheimer's amyloid beta-protein

    J. Biol. Chem.

    (1999)
  • G. Thinakaran et al.

    Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo

    Neuron

    (1996)
  • R. Wang et al.

    The profile of soluble amyloid beta protein in cultured cell media: Detection and quantification of amyloid beta protein and variants by immunoprecipitation–mass spectrometry

    J. Biol. Chem.

    (1996)
  • T. Wisniewski et al.

    Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid

    Neurosci. Lett.

    (1992)
  • G. Xu et al.

    Relationship between abnormal cholesterol synthesis and retarded learning in rats

    Metabolism

    (1998)
  • P.L. Yeagle

    Modulation of membrane function by cholesterol

    Biochimie

    (1991)
  • R.G. Anderson

    The caveolae membrane system

    Annu. Rev. Biochem.

    (1998)
  • P.F. Boston et al.

    Cholesterol and mental disorder

    Br. J. Psychiatry

    (1996)
  • M.S. Bretscher et al.

    Cholesterol and the Golgi apparatus

    Science

    (1993)
  • G.M. Cole et al.

    Lipoprotein effects on Abeta accumulation and degradation by microglia in vitro

    J. Neurosci. Res.

    (1999)
  • K. Duff et al.

    Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1

    Nature

    (1996)
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    1

    To whom correspondence should be addressed at Nathan S. Kline Institute, Dementia Research Group, 140 Old Orangeburg Road, Orangeburg, NY. Fax: (914) 398-5422. E-mail: [email protected].

    2

    Joint last authors.

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