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Cited by 233Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein.

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Knauer, M F, Soreghan, B, Burdick, D, Kosmoski, J, Glabe, C G·1992·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.89.16.7437PMC PMC49725
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Abstract

The A4 or beta protein is a peptide that constitutes the major protein component of senile plaques in Alzheimer disease. The A4/beta protein is derived from a larger, transmembrane amyloid precursor protein (APP). The putative abnormal processing events leading to amyloid accumulation are largely unknown. Here we report that a 42-residue synthetic peptide, beta 1-42, corresponding to one of the longer forms of the A4/beta protein, accumulates in cultured human skin fibroblasts and is stable for at least 3 days. The peptide appears to accumulate intracellularly, since it does not accumulate under conditions that prevent endocytosis and accumulation is correlated with the acquisition of resistance to removal by trypsin digestion. This intracellular accumulation is also correlated with the ability of the peptide to aggregate as determined by SDS/polyacrylamide gel electrophoresis. At low concentrations of the beta 1-42 peptide, which favor the nonaggregated state, no accumulation is observed. Shorter peptide analogs (28 or 39 residues) that are truncated at the C terminus, which lack the ability to aggregate in SDS gels, fail to accumulate. The accumulated intracellular beta 1-42 peptide is in an aggregated state and is contained in a dense organellar compartment that overlaps the distribution of late endosomes or secondary lysosomes. Immunofluorescence of the internalized peptide in permeabilized cells reveals that it is contained in granular deposits, consistent with localization in late endosomes or secondary lysosomes. Sequence analysis indicates that some of the internalized peptide is subject to N-terminal trimming. These results suggest that the aggregated A4/beta protein may be resistant to degradation and suggest that the A4/beta protein may arise, at least in part, by endosomal or lysosomal processing of APP. Our results also suggest that relatively nonspecific proteolysis may be sufficient to generate the A4/beta protein if this part of APP is selectively resistant to proteolysis.

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  • Aβ, when endocytosed, becomes concentrated in acidic endosomal compartments, which promotes amyloid fibril formation and then secretion.

    “Aβ, when endocytosed, becomes concentrated in the acidic endosomal compartments, which promotes amyloid fibril formation and then secretion (Chung et al, 1999; Hu et al, 2009; Knauer et al, 1992).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Knauer et al, 1992

    The abstract reports that endocytosed Aβ1–42 accumulated in cultured fibroblasts in an aggregated state, in a compartment overlapping late endosomes or secondary lysosomes. It does not show that acidity promotes fibril formation or that the accumulated peptide is subsequently secreted. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Knauer, M. F., Soreghan, B., Burdick, D., Kosmoski, J., & Glabe, C. G.
Affiliations
University of California, Irvine (US)
ORCID
Glabe, C G
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1992-08-15
Volume
89
Issue
16
Pages
7437-7441
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.89.16.7437
PMC
PMC49725
OpenAlex
W2069479156
Cited by
233
References
2
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 1 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 7 · 2012: 7
FWCI
5.43
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R35AG007918, AG07918)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD21379, R01HD021379)
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, Alzheimer's disease, amyloid precursor protein, intracellular accumulation, peptide aggregation, endosomal processing, lysosomal degradation, endocytosis, amyloid plaques, dermal fibroblasts
MeSH terms
Amino Acid Sequence, Biological Transport, Cells, Cultured, Fluorescent Antibody Technique, Humans, Infant, Newborn, Molecular Sequence Data, Peptide Fragments, Peptides, Skin, Amyloid beta-Peptides

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