Cited by 867Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition

Iwata, Nobuhisa, Tsubuki, Satoshi, Takaki, Yoshie, Watanabe, Kaori, Sekiguchi, Misaki, Hosoki, Emi, Kawashima-Morishima, Maho, Lee, Hahn-Jun +3 more·2000·Nature Medicine

Abstract

Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion resulted in both biochemical and pathological deposition of endogenous Abeta42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Abeta accumulation.

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Crossref · 10.1038/72237

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  • Neprilysin is the protease shown to most efficiently degrade Aβ and is critical in synaptic activity-induced intraneuronal Aβ42 reduction.

    “The protease shown to most efficiently degrade Aβ, neprilysin [81], was reported to be critical in synaptic activity-induced intraneuronal Aβ42 reduction [190].”

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Authors
Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H.-J., Hama, E., Sekine-Aizawa, Y., & Saido, T. C.
Affiliations
RIKEN Center for Brain Science (JP)
Corresponding author
Saido, Takaomi C.
Venue
Nature Medicine
Published
2000-02
Volume
6
Issue
2
Pages
143-150
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W1998208719
Cited by
867
References
35
Citations by year
2026: 8 · 2025: 17 · 2024: 29 · 2023: 27 · 2022: 16 · 2021: 31 · 2020: 38 · 2019: 29 · 2018: 32 · 2017: 33 · 2016: 28 · 2015: 29 · 2014: 33 · 2013: 31 · 2012: 26
FWCI
30.41
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta, neprilysin, neutral endopeptidase, limited proteolysis, Alzheimer's disease, amyloid deposition, hippocampus, enzyme inhibition
MeSH terms
Amino Acid Sequence, Animals, Chromatography, High Pressure Liquid, Enzyme Inhibitors, Hippocampus, Hydrolysis, Immunohistochemistry, Male, Molecular Sequence Data, Peptide Fragments, Neprilysin, Amyloid beta-Peptides, Rats, Sprague-Dawley, Rats

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