Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk
Open accessAbstract
Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.
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Patients with the gain-of-function LPL polymorphism (S447X) have reduced VLDL-TGs, higher HDL, and reduced amyloid load in the hippocampus.
“In contrast, patients with the gain-of-function LPL polymorphism (S447X) have reduced very-low-density lipoprotein triglycerides (VLDL-TGs), higher high-density lipoproteins (HDL), and reduced amyloid load in the hippocampus [28].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [28]
The Introduction (page unavailable) reports lower VLDL-TG and reduced amyloid plaque formation in patients with S447X; Section 4 identifies it as a gain-of-function variant. The copy does not locate the reduced plaques in the hippocampus or report higher HDL in these patients. Section 4 discusses uptake of HDL, which is not the same as a higher HDL level. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLPL is strongly expressed in the hypothalamus, hippocampus, and striatum.
“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [98]
Section 3, “LPL in the Central Nervous System” (page unavailable), reports LPL in hypothalamic neurons and increased expression in cultures of hypothalamus-derived astrocytes. It does not establish strong expression in the hypothalamus or identify the hippocampus and striatum as sites of strong expression. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe S447X mutation removes residues in the C-terminal tail of LPL, exposing a receptor-binding region that contributes to increased LPL-mediated endocytosis.
“In vitro and modeling studies suggest that the S447X mutation removes residues in the C-terminal tail of LPL, exposing a receptor-binding region that contributes to increased LPL-mediated endocytosis [28,29].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [28]
Several LPL polymorphisms have been linked to increased AD risk.
“In addition, several LPL polymorphisms have been linked to increased AD risk [28].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [28]
LPL is a regulator of brain energy balance.
“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [98]
LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein.
“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [98]
LPL variants are associated with neurite pathology and Alzheimer disease.
“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [98]
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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research
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Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation
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“In addition, several LPL polymorphisms have been linked to increased AD risk [28].”
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- Authors
- D. Bruce, K., Tang, M., Reigan, P., & H. Eckel, R.
- Affiliations
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- University of Colorado Anschutz (US)
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-11-06
- Volume
- 21
- Issue
- 21
- Pages
- 8338
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7664401
- OpenAlex
- W3095753974
- Cited by
- 36
- References
- 97
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 5
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (5KL2TR002534-02)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- lipoprotein lipase, Alzheimer's disease, genetic variants, apolipoprotein C-II, apolipoprotein C-III, microglia, amyloid-beta phagocytosis, lipoprotein metabolism, neuroprotection, triglyceride-rich lipoproteins
- MeSH terms
- Alzheimer Disease, Animals, Humans, Lipoprotein Lipase, Lipoproteins, Macrophages, Mutation, Structure-Activity Relationship, Triglycerides, Amyloid beta-Peptides, Microglia, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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