Molecular Neurobiology

, Volume 47, Issue 1, pp 37–63 | Cite as

Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis

  • M. Maulik
  • D. Westaway
  • J. H. Jhamandas
  • S. Kar


Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.


β-Amyloid peptide Neurotoxicity Lipid rafts Neuronal cholesterol level/distribution 




A disintegrin and metalloproteinase domain containing protein


ATP-binding cassette


Acyl-coenzyme-A cholesterol acyltransferase


Alzheimer’s disease


APP intracellular C-terminal domain


Anterior pharynx defective 1


Apolipoprotein E


Amyloid precursor protein


β-Site APP-cleaving enzyme


Blood–brain barrier


Central nervous system


C-terminal fragment


Insulin-degrading enzyme


Endoplasmic reticulum




High-density lipoprotein




3-Hydroxy-3-methylglutaryl-CoA reductase


Low-density lipoprotein


LDL receptor


LDL receptor-related protein


Liver X receptor


Neurofibrillary tangles


Niemann–Pick type C


Presenilin enhancer 2


Presenilin 1


Presenilin 2


SREBP cleavage-activating protein


Sterol-regulated element-binding protein


Tumor necrosis factor-α-converting enzyme



This was supported by grants from the Canadian Institutes of Health Research. MM is a recipient of the Alberta Innovates Health Research Studentship Award. SK and DW are recipients of Canada Research Chairs.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • M. Maulik
    • 1
    • 2
    • 3
  • D. Westaway
    • 1
    • 2
    • 3
  • J. H. Jhamandas
    • 1
    • 2
    • 3
  • S. Kar
    • 1
    • 2
    • 3
    • 4
  1. 1.Centre for Prions and Protein Folding DiseasesUniversity of AlbertaEdmontonCanada
  2. 2.Centre for NeuroscienceUniversity of AlbertaEdmontonCanada
  3. 3.Department of Medicine (Neurology)University of AlbertaEdmontonCanada
  4. 4.Department of PsychiatryUniversity of AlbertaEdmontonCanada

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