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

Article

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.

Keywords

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

Abbreviations

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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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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