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Cited by 279Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.

Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease

Yu, W.H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb, B.T., Cuervo, A.M., Nixon, R.A.·2004·The International Journal of Biochemistry & Cell Biology
DOI 10.1016/j.biocel.2004.05.010
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Abstract

In Alzheimer's disease (AD), the neuropathologic hallmarks of beta-amyloid deposition and neurofibrillary degeneration are associated with early and progressive pathology of the endosomal-lysosomal system. Abnormalities of autophagy, a major pathway to lysosomes for protein and organelle turnover, include marked accumulations of autophagy-related vesicular compartments (autophagic vacuoles or AVs) in affected neurons. Here, we investigated the possibility that AVs contain the proteases and substrates necessary to cleave the amyloid precursor protein (APP) to A beta peptide that forms beta-amyloid, a key pathogenic factor in AD. AVs were highly purified using a well-established metrizamide gradient procedure from livers of transgenic YAC mice overexpressing wild-type human APP. By Western blot analysis, AVs contained APP, beta CTF - the beta-cleaved carboxyl-terminal domain of APP, and BACE, the protease-mediating beta-cleavage of APP. beta-Secretase activity measured against a fluorogenic peptide was significantly enriched in the AV fraction relative to whole-liver lysate. Compared to other recovered subcellular fractions, AVs exhibited the highest specific activity of gamma-secretase based on a fluorogenic assay and inhibition by a specific inhibitor of gamma-secretase, DAPT. AVs were also the most enriched subcellular fraction in levels of the gamma-secretase components presenilin and nicastrin. Immunoelectron microscopy demonstrated selective immunogold labeling of AVs with antibodies specific for the carboxyl termini of human A beta 40 and A beta 42. These data indicate that AVs are a previously unrecognized and potentially highly active compartment for A beta generation and suggest that the abnormal accumulation of AVs in affected neurons of the AD brain contributes to beta-amyloid deposition.

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Crossref · 10.1016/j.biocel.2004.05.010

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Research works printed but not linked: 2

  1. Cataldo, A. M., Peterhoff, C. M., Schmidt, S. D., Terio, N. B., Duff, K., Beard, M., et al. (2004). Journal of Neuropathology and Experimental Neurology, in press.
  2. Larsen, 2002, Histology and Histopathology, 17, 897

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Metadata

Authors
Yu, W. H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb, B. T., Cuervo, A. M., & Nixon, R. A.
Affiliations
  • Nathan Kline Institute for Psychiatric Research (US)
  • The University of Osaka (JP)
  • Case Western Reserve University (US)
  • Albert Einstein College of Medicine (US)
Corresponding author
Nixon, R.A.
ORCID
Venue
The International Journal of Biochemistry & Cell Biology
Publisher
Elsevier BV
Published
2004-12
Volume
36
Issue
12
Pages
2531-2540
ISSN
1357-2725 (ISSN-L)
DOI
10.1016/j.biocel.2004.05.010
OpenAlex
W2033603289
Cited by
279
References
73
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 16 · 2020: 17 · 2019: 16 · 2018: 9 · 2017: 12 · 2016: 21 · 2015: 28 · 2014: 11 · 2013: 16 · 2012: 19
FWCI
7.30
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The International Journal of Biochemistry & Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (AG17617-05, AG-021904, P01AG017617)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
autophagosomes, amyloid precursor protein, amyloid-beta, Alzheimer's disease, beta-secretase, gamma-secretase, BACE, presenilin, nicastrin, autophagy, lysosomal system, endolysosomal pathway, subcellular fractionation
MeSH terms
Alzheimer Disease, Animals, Autophagy, Humans, Liver, Mice, Transgenic, Neurons, Endopeptidases, Vacuoles, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Amyloid Precursor Protein Secretases

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