Cited by 158Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease

Kumar-Singh, S.·2000·Human Molecular Genetics

DOI 10.1093/hmg/9.18.2589

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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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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
DOI: 10.1093/hmg/9.18.2589
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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Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer's disease

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