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.

doi:10.1016/j.biocel.2004.05.010

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

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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Autophagy: Basic Principles and Relevance to Disease
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Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death.
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Does Autophagy Contribute To Cell Death?
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Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes
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Autophagy in neurodegenerative disease: friend, foe or turncoat?
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Insulin‐like growth factor‐1 and TNF‐α regulate autophagy through c‐jun N‐terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells
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Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia–ischaemia
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Substrate specificity of γ-secretase and other intramembrane proteases
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The up‐regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α
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Pathological apoptosis in the developing brain
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Alzheimer's Disease: A Lesson from Mitochondrial Dysfunction
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Reversal effects of crocin on amyloid β-induced memory deficit: Modification of autophagy or apoptosis markers
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Structure of Transmembrane Domain of Lysosome-associated Membrane Protein Type 2a (LAMP-2A) Reveals Key Features for Substrate Specificity in Chaperone-mediated Autophagy*
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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: Yu, W.H.
Kumar, A.
Uchiyama, Y.
Lamb, B.T.
Cuervo, A.M.
Nixon, R.A.
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The International Journal of Biochemistry & Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG17617-05, AG-021904, P01AG017617)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Epidemiology › 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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Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease

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