Role of amyloid beta in lipid homeostasis
Abstract
Alzheimer's disease (AD), the most common neurodegenerative disorder, which affects more than 35 million people worldwide, is characterized by a massive accumulation of tangles and amyloid plaques. Several risk factors linked to lipid homeostasis have been identified. Apolipoprotein E (ApoE), which also has a strong impact in coronary artery disease, is besides aging the most prominent risk factor in sporadic AD. High levels of lipoproteins and cholesterol increase the risk of AD and some cholesterol lowering drugs like statins seem to correlate with a reduced risk for dementia. Moreover, cholesterol increases amyloid beta (Abeta) production, which is derived from amyloid precursor protein (APP) by proteolytic processing. Beside cholesterol, other lipids that strongly modulate APP processing could be identified and interestingly the APP cleavage products itself regulate lipid homeostasis resulting in complex regulatory feedback cycles. Here, we review the mechanistic link of cholesterol and sphingolipid homeostasis and APP processing and the consequence of this bidirectional link for and in AD. Although cholesterol is the best studied brain lipid in AD, many other lipids are involved in the Abeta-lipid regulatory system and some of these lipids exceed the cholesterol effect on Abeta production [1-5]. This involvement is bidirectional. On the one hand, lipids control APP processing and, on the other hand, APP processing controls the levels of several key lipids [6, 7]. Beside the physiological function of APP processing in lipid homeostasis, under pathological conditions like AD, these regulating (feedback-) cycles are dysfunctional. Additionally, mutual influence of lipids and APP processing raises the question if altered lipid homeostasis is the cause or consequence of AD.
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APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3.
“APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3 [8–10].”
APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms, including influencing APP processing via effects on lipid metabolism and modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes.
“APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms: 1) influencing APP processing via effects on lipid metabolism [8–10], and 2) modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes [11, 12].”
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- Authors
- Grösgen, S., Grimm, M. O. W., Frieß, P., & Hartmann, T.
- Affiliations
- Saarland University (DE)
- Corresponding author
- Hartmann, Tobias
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 1801
- Issue
- 8
- Pages
- 966-974
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2021148483
- Cited by
- 90
- References
- 140
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 8 · 2015: 6 · 2014: 3 · 2013: 5 · 2012: 16
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, lipid homeostasis, Alzheimer's disease, apolipoprotein E, cholesterol, sphingolipids, APP processing, lipoproteins, statins, amyloid plaques, feedback regulation
- MeSH terms
- Alzheimer Disease, Animals, Cholesterol, Homeostasis, Humans, Lipids, Models, Biological, Protein Processing, Post-Translational, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Lipid Metabolism, Amyloid Precursor Protein Secretases
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