Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides
Open accessAbstract
Alzheimer's disease (AD) is characterized by the presence of toxic protein aggregates or plaques composed of the amyloid β (Aβ) peptide. Various lengths of Aβ peptide are generated by proteolytic cleavages of the amyloid precursor protein (APP). Mutations in many familial AD-associated genes affect the production of the longer Aβ42 variant that preferentially accumulates in plaques. In the case of sporadic or late-onset AD, which accounts for greater than 95% of cases, several genes are implicated in increasing the risk, but whether they also cause the disease by altering amyloid levels is currently unknown. Through loss of function studies in a model cell line, here RNAi-mediated silencing of several late onset AD genes affected Aβ levels is shown. However, unlike the genes underlying familial AD, late onset AD-susceptibility genes do not specifically alter the Aβ42/40 ratios and suggest that these genes probably contribute to AD through distinct mechanisms.
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RNAi-mediated silencing of BIN1 expression in HeLa cells resulted in a 1.5-fold increase in Aβ40 secretion and a 2-fold increase in Aβ42 secretion.
“RNAi-mediated silencing of BIN1 expression in HeLa cells resulted in a 1.5- and 2-fold increase in Aβ40 and Aβ42 secretion, respectively [59].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [59]
Bin1 RNAi failed to affect Ab production in HeLa cells expressing Swedish mutant APP.
“This is also consistent with a previous report that Bin1 RNAi failed to affect Ab production in HeLa cells expressing Swedish mutant APP (39), which is cleaved by BACE1 in early secretory compartments such as the trans-Golgi network (40).”
From BIN1 regulates BACE1 intracellular trafficking and amyloid-β production (2016) · cites this paper as [39]
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Alzheimer’s disease: Clinical trials and drug development
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Metal Ions in Alzheimer’s Disease: A Key Role or Not?
Liu, Y., Nguyen, M., Robert, A., & Meunier, B. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00248 · Cited by 353 · see citing works
De Rossi, P., Buggia-Prévot, V., Clayton, B. L. L., Vasquez, J. B., van Sanford, C., Andrew, R. J., Lesnick, R., Botté, A., Deyts, C., Salem, S., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0124-1 · Cited by 151 · see citing works
“5- and 2-fold increase in Aβ40 and Aβ42 secretion, respectively [59].”
Chakrabarti, S., Kumar Khemka, V., Banerjee, A., Chatterjee, G., Ganguly, A., & Biswas, A. (2015) · Aging and disease · doi:10.14336/ad.2014.002 · Cited by 134 · see citing works
ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing
Satoh, K., Abe-Dohmae, S., Yokoyama, S., St George-Hyslop, P., & Fraser, P. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655076 · Cited by 128 · see citing works
BIN1 regulates BACE1 intracellular trafficking and amyloid-β production
Miyagawa, T., Ebinuma, I., Morohashi, Y., Hori, Y., Young Chang, M., Hattori, H., Maehara, T., Yokoshima, S., Fukuyama, T., Tsuji, S., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw146 · Cited by 95 · see citing works
Mechanistic Insights for Drug Repurposing and the Design of Hybrid Drugs for Alzheimer’s Disease
Padhi, D., & Govindaraju, T. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00335 · Cited by 47 · see citing works
- Authors
- Bali, J., Gheinani, A. H., Zurbriggen, S., & Rajendran, L.
- Affiliations
- University of Zurich (CH)
- Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-04
- Volume
- 109
- Issue
- 38
- Pages
- 15307-15311
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3458335
- OpenAlex
- W2160277958
- Cited by
- 107
- References
- 3
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 14 · 2023: 20 · 2022: 10 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 4
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › 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
- sporadic Alzheimer's disease, late-onset Alzheimer's disease, amyloid-beta, Aβ42/Aβ40 ratio, amyloid precursor protein, APP cleavage, risk genes, RNA interference, loss of function, amyloid plaques
- MeSH terms
- Aged, Alzheimer Disease, Epistasis, Genetic, HeLa Cells, Humans, Models, Genetic, Mutation, Peptide Fragments, Risk, Genetic Variation, Cystatins, Amyloid beta-Peptides, Age of Onset, Genetic Predisposition to Disease, Gene Silencing, RNA Interference, Cell Proliferation, Genome-Wide Association Study, Plaque, Amyloid
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