Cholesterol Metabolism in Neurodegenerative Disease Mechanisms

Cholesterol is a pivotal lipid in the central nervous system, essential for membrane integrity, synaptic transmission and myelin formation. Unlike peripheral tissues, brain cholesterol is synthesised locally by neurons and glia, with export pathways relying on enzymatic conversion into oxysterols that traverse the blood–brain barrier. Homeostatic balance is maintained through coordinated synthesis by astrocytes, uptake via apolipoprotein E-containing lipoproteins and catabolism by cholesterol 24-hydroxylase (CYP46A1). Dysregulation of this cycle contributes to the onset and progression of Alzheimer’s, Parkinson’s and other neurodegenerative disorders. Excess cholesterol or altered oxysterol profiles can perturb membrane microdomains, compromise synaptic plasticity and promote aggregation of amyloid-beta and tau. Genetic variants in ApoE and sterol-metabolising enzymes further modulate disease risk. Emerging evidence highlights the role of glia–neuron interactions in sterol transport and reveals cell type-specific vulnerabilities. Circulating levels of 24S-hydroxycholesterol serve as biomarkers of central cholesterol turnover, while strategies targeting enzyme modulators or lipid-lowering approaches hold promise for therapeutic intervention in diverse neurodegenerative conditions.

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Cholesterol Metabolism in Neurodegenerative Disease Mechanisms publication trend

The graph below shows the total number of articles in cholesterol metabolism in neurodegenerative disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Oxysterol: An oxidised derivative of cholesterol capable of crossing the blood–brain barrier and modulating sterol homeostasis.

Apolipoprotein E (ApoE): A lipid-binding protein that mediates cholesterol transport and redistribution within the brain.

Cholesteryl ester: A storage form of cholesterol formed by esterification to a fatty acid, accumulating under conditions of excess sterol.

CYP46A1: Cholesterol 24-hydroxylase, an enzyme in neurons that converts cholesterol into 24S-hydroxycholesterol for cerebral elimination.

Membrane raft: A cholesterol-rich microdomain in the plasma membrane that organises signalling molecules and protein clustering.

References

1. Cholesterol Metabolism in Aging and Age-Related Disorders. Annual Review of Neuroscience (2023).
2. Cholesterol imbalance and neurotransmission defects in neurodegeneration. Experimental & Molecular Medicine (2024).
3. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons. Cell Stem Cell (2019).
4. Cholesterol metabolism and homeostasis in the brain. Protein & Cell (2015).
5. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Disease Models & Mechanisms (2012).
6. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. Journal of Lipid Research (1998).
7. Knockout of the Cholesterol 24-Hydroxylase Gene in Mice Reveals a Brain-specific Mechanism of Cholesterol Turnover*. Journal of Biological Chemistry (2003).
8. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. Journal of Lipid Research (2000).