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

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

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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Crossref · 10.1093/hmg/9.18.2589

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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.

    “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].”

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Authors
Kumar-Singh, S.
Venue
Human Molecular Genetics
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
  • 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
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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