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Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets

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Abstract

Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.

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Abbreviations

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

HD:

Huntington’s disease

BBB:

Blood–brain barrier

ER:

Endoplasmic reticulum

HMG-CoA:

3-Hydroxy-3-methylglutaryl CoA

DE:

Desmosterol

DHCR24:

24-Dehydrocholesterol reductase

DHCR7:

7-Dehydrocholesterol reductase

LT:

Lathosterol

7D:

7-Dehydrocholesterol

PM:

Plasma membrane

SREBP-2:

Sterol regulatory element-binding protein

SCAP:

SREBP cleavage-activating protein

SRE:

Sterol regulatory elements

HDL:

High-density lipoprotein cholesterol

LDL:

Low-density lipoprotein cholesterol

VLDL:

Very-low-density lipoprotein cholesterol

APOE:

Apolipoprotein E

ABC transporters:

ATP-binding cassette (ABC) transporters

LDLR:

Low-density lipoprotein family receptors

ACAT1/SOAT1:

Acyltransferase 1

CSF:

Cerebrospinal fluid

24-OHC:

24-Hydroxycholesterol

Aβ:

Amyloid-β

ACID:

APP intracellular domain

APP:

Amyloid precursor protein

27-OHC:

27-Hydroxylcholesterol

CYP27A1:

Sterol 27-hydroxylase

RAS:

Renin–angiotensin system

PLTP:

Phospholipid transporters

SNpc:

Substantia nigra pars compacta

LBs:

Lewy bodies

ApoA1:

Apolipoprotein A-I

PON1:

Oxygenase 1

VMAT2:

Vesicular monoamine transporter 2

DAT:

Dopamine transporter

mβCD:

Methyl-β-cyclodextrin

LXRs:

Liver X receptors

TH:

Tyrosine hydroxylase

NMDAR1:

N-methyl-d-aspartic acid receptor 1

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

NO:

Nitric oxide

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81822016 and 81771382) and the Natural Science Foundation of Hubei Province (No. 2018CFA036) to Z. Zhang.

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Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Lijun Dai, Li Zou, Lanxia Meng, Mingmin Yan & Zhentao Zhang

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, China

    Guifen Qiang

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  1. Lijun Dai
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  2. Li Zou
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  3. Lanxia Meng
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  6. Zhentao Zhang
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LJD conceived and drafted the manuscript. LZ helped to draw the schematics. The final manuscript was read and approved by all authors.

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Correspondence to Zhentao Zhang.

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Dai, L., Zou, L., Meng, L. et al. Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets. Mol Neurobiol 58, 2183–2201 (2021). https://doi.org/10.1007/s12035-020-02232-6

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