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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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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DOI: https://doi.org/10.1007/s12035-012-8337-y