Intracellular Accumulation of Insoluble, Newly Synthesized Aβn-42 in Amyloid Precursor Protein-transfected Cells That Have Been Treated with Aβ1–42
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Our early study indicates that intracellular Abeta1-42 aggregates are resistant to degradation and accumulate as an insoluble residue in lysosomes, where they alter the normal catabolism of amyloid precursor protein (APP) to cause the accumulation of insoluble APP and amyloidogenic fragments. In this study, we examined whether the addition of exogenous Abeta1-42 also leads to the accumulation of newly synthesized intracellular Abeta. Here we describe that newly synthesized Abeta, especially Abetan-42, is generated from metabolically labeled APP and accumulates in the insoluble fraction of cell lysates after Abeta1-42 treatment. These results suggest that intracellular Abeta may derive from a solid phase, intracellular pathway. In contrast to the pathway that primarily produces secreted Abeta1-40, the solid-phase intracellular pathway preferentially produces Abetan-42 with ragged amino termini. Biochemical studies and amino acid sequencing analyses indicate that these intracellular Abeta also share the same types of Abeta structures that accumulate in the brain of Alzheimer's disease patients, suggesting that a significant fraction of the amyloid deposits in Alzheimer's disease may arise by this solid-phase pathway.
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Extracellular Aβ1-42 leads to marked up-regulation of endogenously generated Aβ42, which also occurs in neurons.
“Work in the 1990s had shown that extracellular Aβ1-42 led to marked up-regulation of endogenously generated Aβ42 [51, 211], which also occurs in neurons [190].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [211]
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- Authors
- Yang, A. J., Chandswangbhuvana, D., Shu, T., Henschen, A., & Glabe, C. G.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- University of California, Irvine (US)
- Corresponding author
- Yang, Austin J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-07
- Volume
- 274
- Issue
- 29
- Pages
- 20650-20656
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2037197109
- Cited by
- 108
- References
- 39
- Citations by year
- 2026: 1 · 2025: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 1 · 2013: 5 · 2012: 10
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (AG00538)
- National Institute on Aging (AG 00538)
- 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
- amyloid-beta 42, amyloid precursor protein
- MeSH terms
- Alzheimer Disease, Autoradiography, Cells, Cultured, Chromatography, Gel, Chromatography, High Pressure Liquid, Peptide Fragments, Precipitin Tests, Transfection, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
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