Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition
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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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].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [81]
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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
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 ›
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