CoChat
Sign Up
Cited by 220Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function

Open access
Suh, Jaehong, Choi, Se Hoon, Romano, Donna M., Gannon, Moira A., Lesinski, Andrea N., Kim, Doo Yeon, Tanzi, Rudolph E.·2013·Neuron
DOI 10.1016/j.neuron.2013.08.035PMC PMC4105199
Open this paper in CoChat — free accountOpen PDF

Abstract

The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by α-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated α-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished α-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2013.08.035

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Rare mutations in amyloid precursor protein (APP), presenilin (PSEN) 1 and 2, ADAM10, and ADAM17 trigger Aβ plaque accumulation and are sufficient to induce the full biochemical and morphological signature of AD.

    “Rare mutations in amyloid precursor protein (APP), presenilin (PSEN) 1 and 2 (Karch et al., 2014), ADAM10 (Suh et al., 2013), and ADAM17 (Hartl et al., 2018) trigger Aβ plaque accumulation and are sufficient to induce the full biochemical and morphological signature of AD.”

    From The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019) · cites this paper as Suh et al., 2013

    The Discussion reports that rare ADAM10 mutations increased Aβ levels, plaque load, and reactive gliosis in Tg2576 AD mice. But those mice also carried an APP mutation; the paper does not establish that ADAM10 mutations alone are sufficient to produce the full biochemical and morphological signature of AD. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ADAM10 is a susceptibility gene for AD.

    “establishing ADAM10 as a susceptibility gene for AD.”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [11]

  • Mutations of ADAM10 that reduce its activity enhance amyloidogenic APP processing and Aβ deposition and are linked to late-onset AD.

    “Mutations of ADAM10 that reduce its activity and enhance amyloidogenic APP processing and Aβ deposition have recently been linked to late-onset AD (LOAD) (10, 11), establishing ADAM10 as a susceptibility gene for AD.”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [11]

  • Two rare ADAM10 alterations segregating with disease in LOAD families increased Aβ plaque load in 'Alzheimer-like' mice, with diminished α-secretase activity from the alterations probably the causal mechanism.

    “two rare ADAM10 alterations segregating with disease in LOAD families increased Aβ plaque load in ‘Alzheimer-like’ mice, with diminished α-secretase activity from the alterations probably the causal mechanism19,44.”

    From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [44]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

2 retracted

Flagged first, then by citations

1 of the 49 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Suh, J., Choi, S. H., Romano, D. M., Gannon, M. A., Lesinski, A. N., Kim, D. Y., & Tanzi, R. E.
Affiliations
Harvard University (US)
Corresponding author
Tanzi, Rudolph E.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2013-10
Volume
80
Issue
2
Pages
385-401
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2013.08.035
PMC
PMC4105199
OpenAlex
W1979909831
Cited by
217
References
49
Citations by year
2026: 6 · 2025: 6 · 2024: 16 · 2023: 13 · 2022: 16 · 2021: 13 · 2020: 23 · 2019: 25 · 2018: 20 · 2017: 16 · 2016: 21 · 2015: 24 · 2014: 15 · 2013: 3
FWCI
14.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG041856, P50AG005134, P30AG062421)
  • National Institute of Mental Health (R01MH060009)
  • National Institute of Neurological Disorders and Stroke (R01NS045860)
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
ADAM10, missense mutations, amyloid precursor protein, amyloid-beta deposition, late-onset Alzheimer's disease, APP processing, beta-secretase, amyloid plaques, reactive gliosis, adult hippocampal neurogenesis, Tg2576 mice, therapeutic target
MeSH terms
ADAM10 Protein, Alzheimer Disease, Animals, Brain, Female, Gliosis, Hippocampus, Humans, Male, Membrane Proteins, Mice, Transgenic, Amyloid beta-Peptides, Molecular Chaperones, Genetic Predisposition to Disease, Mutation, Missense, Mice, ADAM Proteins, Amyloid Precursor Protein Secretases, Neurogenesis, Plaque, Amyloid

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review