The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease
Abstract
Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid beta-peptide (A beta(42)) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid A beta(42) deposits have to mature in the presence of A beta(40) into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving gamma-secretase cleavages of APP. The mutation had the most drastic effect on A beta(42)/A beta(40) ratio in vitro of approximately 11-fold, simultaneously increasing A beta(42) and decreasing A beta(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta(42) in complete absence of A beta(40). These data indicate that N-truncated A beta(42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length A beta(42 )by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta(42).
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“FAD mutations can even decrease secretion of the most abundantly released Aβ isoform, Aβ40, while still increasing the Aβ42 to Aβ40 ratio [90, 134, 173].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [90]
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Alzheimer disease models and human neuropathology: similarities and differences
Duyckaerts, C., Potier, M.-C., & Delatour, B. (2008) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 375
Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0679-9 · Cited by 372
BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease
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Crowther, D. C., Kinghorn, K. J., Miranda, E., Page, R., Curry, J. A., Duthie, F., Gubb, D., & Lomas, D. A. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2004.12.025 · Cited by 369
Molecular Basis of Familial and Sporadic Alzheimer's Disease
Dorszewska, J., Prendecki, M., Oczkowska, A., Dezor, M., & Kozubski, W. P. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160314150501 · Cited by 340
Metadata
- Authors
- Kumar-Singh, S.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-11-01
- Volume
- 9
- Issue
- 18
- Pages
- 2589-2598
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2126690234
- Cited by
- 158
- References
- 51
- Citations by year
- 2025: 8 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 3 · 2017: 4 · 2016: 10 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 5
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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 42, gamma-secretase, APP processing, amyloid precursor protein, Aβ40
- MeSH terms
- Alzheimer Disease, Cell Line, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Male, Pedigree, Peptide Fragments, Endopeptidases, Protein Processing, Post-Translational, Solubility, Transfection, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Amino Acid Substitution, Mutation, Missense, Amyloid Precursor Protein Secretases, Plaque, Amyloid
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