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APP Function and Lipids: A Bidirectional Link
Open accessAbstract
Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) peptides, are one of the major histopathological hallmarks of Alzheimer’s disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) ɛ4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations protective lipids being able to decrease Aβ generation and also potential negative lipids in respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipid metabolism pathways.
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“Indeed, there is evidence that alternative APP-derived fragments as well as APP itself play important roles in the modulation of immune cell activation [160], protein clearance [161], and lipid homeostasis [162].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [162]
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Association of Alzheimer disease pathology with abnormal lipid metabolism
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Long-chain polyunsaturated fatty acids in maternal and infant nutrition
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Human brain gangliosides in development, aging and disease
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Flagged first, then by citations
1 of the 265 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- World Alzheimer Report, 2015, Alzheimer’s Disease International
Cited by
Sorted by citations
Surgery, neuroinflammation and cognitive impairment
Alam, A., Hana, Z., Jin, Z., Suen, K. C., & Ma, D. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.10.021 · Cited by 495
Application of Metabolomics in Alzheimer’s Disease
Wilkins, J. M., & Trushina, E. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2017.00719 · Cited by 268
Yang, J., Wang, Z., Cai, H.-Y., Li, Y., Hu, M.-M., Wu, M., & Qi, J. (2018) · Neuroscience Bulletin · doi:10.1007/s12264-018-0268-9 · Cited by 168
van Kruining, D., Luo, Q., van Echten‐Deckert, G., Mielke, M. M., Bowman, A. P., Ellis, S. R., Oliveira, T. G., & Martínez‐Martínez, P. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.04.009 · Cited by 138
Akyol, S., Ugur, Z., Yılmaz, A., Ustun, I., Gorti, S. K. K., Oh, K., McGuinness, B., Passmore, P., Kehoe, P. G., Maddens, M. E., et al. (2021) · Cells · doi:10.3390/cells10102591 · Cited by 138
Metadata
- Authors
- Grimm, M. O. W., Mett, J., Grimm, H. S., & Hartmann, T.
- Affiliations
- Saarland University (DE)
- Corresponding author
- Grimm, Marcus O. W.
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2017-03-10
- Volume
- 10
- Pages
- 63-63
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC5344993
- OpenAlex
- W2594288299
- Cited by
- 104
- References
- 265
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 5 · 2023: 17 · 2022: 7 · 2021: 19 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 4
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta, amyloid precursor protein, APOE ε4, lipid metabolism, beta-secretase, gamma-secretase, alpha-secretase, APP intracellular domain, lipid homeostasis, fatty acids, neuritic plaques, lipid dysregulation
About these checks
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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