Cited by 638Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Postina, Rolf, Schroeder, Anja, Dewachter, Ilse, Bohl, Juergen, Schmitt, Ulrich, Kojro, Elzbieta, Prinzen, Claudia, Endres, Kristina +7 more·2004·Journal of Clinical Investigation

Abstract

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.

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Crossref · 10.1172/jci20864

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Authors
Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., Flamez, P., Dequenne, A., Godaux, E., van Leuven, F., & Fahrenholz, F.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • KU Leuven (BE)
  • University of Mons (BE)
Corresponding author
Fahrenholz, Falk
Venue
Journal of Clinical Investigation
Published
2004-05-15
Volume
113
Issue
10
Pages
1456-1464
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2132810311
Cited by
638
References
56
Citations by year
2026: 6 · 2025: 7 · 2024: 19 · 2023: 25 · 2022: 18 · 2021: 30 · 2020: 26 · 2019: 31 · 2018: 29 · 2017: 34 · 2016: 34 · 2015: 34 · 2014: 37 · 2013: 39 · 2012: 31
FWCI
20.82
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Fonds Wetenschappelijk Onderzoek
  • Fritz Thyssen Stiftung
  • KU Leuven
  • Vlaamse regering
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, ADAM10, alpha-secretase, amyloid-beta, amyloid plaques, amyloid precursor protein, soluble APP alpha, long-term potentiation, cognitive impairment, hippocampus, non-amyloidogenic pathway, therapeutic target
MeSH terms
Alzheimer Disease, Amyloid, Amyloidosis, Animals, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Endopeptidases, Gene Expression, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases

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