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

Abstract

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.

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Abbreviations

Aβ:

β-Amyloid

ADAM:

A disintegrin and metalloproteinase domain containing protein

ABC:

ATP-binding cassette

ACAT:

Acyl-coenzyme-A cholesterol acyltransferase

AD:

Alzheimer’s disease

AICD:

APP intracellular C-terminal domain

APH-1:

Anterior pharynx defective 1

ApoE:

Apolipoprotein E

APP:

Amyloid precursor protein

BACE:

β-Site APP-cleaving enzyme

BBB:

Blood–brain barrier

CNS:

Central nervous system

CTF:

C-terminal fragment

IDE:

Insulin-degrading enzyme

ER:

Endoplasmic reticulum

GPI:

Glycosylphosphatidylinositol

HDL:

High-density lipoprotein

HMG-CoA:

3-Hydroxy-3-methylglutaryl-CoA

HMGCR:

3-Hydroxy-3-methylglutaryl-CoA reductase

LDL:

Low-density lipoprotein

LDLR:

LDL receptor

LRP:

LDL receptor-related protein

LXR:

Liver X receptor

NFTs:

Neurofibrillary tangles

NPC:

Niemann–Pick type C

PEN-2:

Presenilin enhancer 2

PS1:

Presenilin 1

PS2:

Presenilin 2

SCAP:

SREBP cleavage-activating protein

SREBP:

Sterol-regulated element-binding protein

TACE:

Tumor necrosis factor-α-converting enzyme

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Acknowledgments

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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Maulik, M., Westaway, D., Jhamandas, J.H. et al. Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis. Mol Neurobiol 47, 37–63 (2013). https://doi.org/10.1007/s12035-012-8337-y

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Keywords

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