Emerging role of HDL in brain cholesterol metabolism and neurodegenerative disorders
Abstract
High-density lipoproteins (HDL) play a key role in cholesterol homeostasis maintenance in the central nervous system (CNS), by carrying newly synthesized cholesterol from astrocytes to neurons, to support their lipid-related physiological functions. As occurs for plasma HDL, brain lipoproteins are assembled through the activity of membrane cholesterol transporters, undergo remodeling mediated by specific enzymes and transport proteins, and finally deliver cholesterol to neurons by a receptor-mediated internalization process. A growing number of evidences indicates a strong association between alterations of CNS cholesterol homeostasis and neurodegenerative disorders, in particular Alzheimer's disease (AD), and a possible role in this relationship may be played by defects in brain HDL metabolism. In the present review, we summarize and critically examine the current state of knowledge on major modifications of HDL and HDL-mediated brain cholesterol transport in AD, by taking into consideration the individual steps of this process. We also describe potential and encouraging HDL-based therapies that could represent new therapeutic strategies for AD treatment. Finally, we revise the main plasma and brain HDL modifications in other neurodegenerative disorders including Parkinson's disease (PD), Huntington's disease (HD), and frontotemporal dementia (FTD).
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In the cerebrospinal fluid (CSF), HDL-like LNPs predominate, although their major protein constituent is ApoE, not ApoA-I.
“In the cerebrospinal fluid (CSF), HDL-like LNPs predominate, although their major protein constituent is ApoE, not ApoA-I.11, 12”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [11]
A similar mechanism may occur in the brain where lipoproteins are HDL-like, and low concentration of ApoE on HDL lacking ApoC3 may affect neuronal cholesterol uptake and clearance of Aβ and tau mediated by ApoE-binding receptors, eventually affecting cognitive function and Alzheimer's disease risk.
“A similar mechanism may occur in the brain where lipoproteins are HDL-like [33] and low concentration of ApoE on HDL lacking ApoC3 may affect the neuronal cholesterol uptake and clearance of Aβ and tau mediated by ApoE-binding receptors and eventually affecting cognitive function and AD risk.”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [33]
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- Authors
- Turri, M., Marchi, C., Adorni, M. P., Calabresi, L., & Zimetti, F.
- Affiliations
- University of Milan (IT)
- University of Parma (IT)
- Corresponding author
- Calabresi, Laura
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 1867
- Issue
- 5
- Pages
- 159123
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W4211167918
- Cited by
- 54
- References
- 34
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 11 · 2023: 15 · 2022: 2
- FWCI
- 10.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- high-density lipoprotein, brain cholesterol metabolism, cholesterol homeostasis, neurodegenerative diseases, Alzheimer's disease, cholesterol transport, Parkinson's disease, Huntington's disease, frontotemporal dementia
- MeSH terms
- Alzheimer Disease, Brain, Cholesterol, Humans, Lipoproteins, HDL, Cholesterol, HDL, Neurodegenerative Diseases
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