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Cited by 344Cholesterol and Lipid MetabolismLysosomal Storage Disorders ResearchAlzheimer's disease research and treatments

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Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

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Vance, Jean E.·2012·Disease Models & Mechanisms
DOI 10.1242/dmm.010124PMC PMC3484857
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Abstract

Summary: Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

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Figures

Fig. 1. Cholesterol biosynthesis. Cholesterol is synthesized from acetyl-CoA. A key intermediate in the pathway, mevalonic acid, is produced from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by the rate-limiting enzyme of the pathway, HMG-CoA reductase; this enzyme is inhibited by the cholesterol-lowering drugs, the statins. In the final step of the pathway, 7-dehydrocholesterol is converted to cholesterol by the enzyme 7-dehydrocholesterol reductase, the defective enzyme in SLOS. Hydroxylated derivatives of cholesterol, such as 24-, 25- and 27-hydroxycholesterol, are produced from cholesterol by specific hydroxylases, such as CYP46.
Fig. 1. Cholesterol biosynthesis. Cholesterol is synthesized from acetyl-CoA. A key intermediate in the pathway, mevalonic acid, is produced from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by the rate-limiting enzyme of the pathway, HMG-CoA reductase; this enzyme is inhibited by the cholesterol-lowering drugs, the statins. In the final step of the pathway, 7-dehydrocholesterol is converted to cholesterol by the enzyme 7-dehydrocholesterol reductase, the defective enzyme in SLOS. Hydroxylated derivatives of cholesterol, such as 24-, 25- and 27-hydroxycholesterol, are produced from cholesterol by specific hydroxylases, such as CYP46.CC BY-NC-SA · PubMed Central
Fig. 2. APOE-containing lipoproteins transport cholesterol from astrocytes to neurons. Glial cells, primarily astrocytes, but also microglia, secrete APOE, which acquires cholesterol and phospholipids, thereby forming APOE-containing lipoproteins. These are delivered to neurons where they are endocytosed via cell surface receptors (members of the LDL receptor family). Consequently, cholesterol is delivered to the neurons. Some APOE receptors also function as signaling receptors.
Fig. 2. APOE-containing lipoproteins transport cholesterol from astrocytes to neurons. Glial cells, primarily astrocytes, but also microglia, secrete APOE, which acquires cholesterol and phospholipids, thereby forming APOE-containing lipoproteins. These are delivered to neurons where they are endocytosed via cell surface receptors (members of the LDL receptor family). Consequently, cholesterol is delivered to the neurons. Some APOE receptors also function as signaling receptors.CC BY-NC-SA · PubMed Central
Fig. 3. NPC1 and NPC2 mediate cholesterol export from late endosomes and/or lysosomes. Cholesterol (blue oval) is released from endocytosed LDLs and binds to NPC2 (red), a soluble protein in the lysosomal lumen. Subsequently, NPC2 directly transfers the cholesterol to NPC1 (yellow), located in the limiting membrane of the lysosome, so that the hydrophobic cholesterol molecule does not have to travel through the aqueous milieu of the lysosomal lumen. Ultimately, the cholesterol is exported from the lysosomal membrane and is transported via the cytosol to the endoplasmic reticulum and plasma membrane by unknown mechanisms.
Fig. 3. NPC1 and NPC2 mediate cholesterol export from late endosomes and/or lysosomes. Cholesterol (blue oval) is released from endocytosed LDLs and binds to NPC2 (red), a soluble protein in the lysosomal lumen. Subsequently, NPC2 directly transfers the cholesterol to NPC1 (yellow), located in the limiting membrane of the lysosome, so that the hydrophobic cholesterol molecule does not have to travel through the aqueous milieu of the lysosomal lumen. Ultimately, the cholesterol is exported from the lysosomal membrane and is transported via the cytosol to the endoplasmic reticulum and plasma membrane by unknown mechanisms.CC BY-NC-SA · PubMed Central
Fig. 4. Processing of APP. In the non-amyloidogenic pathway of APP processing, APP is proteolytically cleaved within the Aβ region (red box) by α-secretase (α). In the amyloidogenic pathway, APP is cleaved first by β-secretase (β) and subsequently by γ-secretase (γ) to generate the pathological Aβ fragments that accumulate in brains of individuals with AD.
Fig. 4. Processing of APP. In the non-amyloidogenic pathway of APP processing, APP is proteolytically cleaved within the Aβ region (red box) by α-secretase (α). In the amyloidogenic pathway, APP is cleaved first by β-secretase (β) and subsequently by γ-secretase (γ) to generate the pathological Aβ fragments that accumulate in brains of individuals with AD.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Vance, J. E.
Affiliations
University of Alberta (CA)
Corresponding author
Vance, Jean E.
Venue
Disease Models & Mechanisms
Publisher
The Company of Biologists
Published
2012-01-01
Volume
5
Issue
6
Pages
746-55
ISSN
  • 1754-8403 (ISSN-L)
  • 1754-8411
DOI
10.1242/dmm.010124
PMC
PMC3484857
OpenAlex
W2166069871
Cited by
342
References
123
Citations by year
2026: 2 · 2025: 13 · 2024: 26 · 2023: 33 · 2022: 27 · 2021: 37 · 2020: 34 · 2019: 29 · 2018: 24 · 2017: 24 · 2016: 18 · 2015: 28 · 2014: 31 · 2013: 15 · 2012: 1
FWCI
4.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Disease Models & Mechanisms (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • HighWire Press Open Archive (submittedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
cholesterol homeostasis, brain cholesterol metabolism, neurodegenerative diseases, Alzheimer's disease, Huntington's disease, Parkinson's disease, Niemann-Pick disease type C, Smith-Lemli-Opitz syndrome, apolipoprotein E, APOE ε4, statins, blood-brain barrier, cholesterol biosynthesis, cholesterol transport
MeSH terms
Animals, Brain, Cholesterol, Humans, Models, Biological, Neurodegenerative Diseases

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