Cited by 290Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Detection of a Novel Intraneuronal Pool of Insoluble Amyloid β Protein that Accumulates with Time in Culture

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Skovronsky, Daniel M., Doms, Robert W., Lee, Virginia M.-Y.·1998·The Journal of Cell Biology

Abstract

The amyloid-β peptide (Aβ) is produced at several sites within cultured human NT2N neurons with Aβ1-42 specifically generated in the endoplasmic reticulum/intermediate compartment. Since Aβ is found as insoluble deposits in senile plaques of the AD brain, and the Aβ peptide can polymerize into insoluble fibrils in vitro, we examined the possibility that Aβ1-40, and particularly the more highly amyloidogenic Aβ1-42, accumulate in an insoluble pool within NT2N neurons. Remarkably, we found that formic acid extraction of the NT2N cells solubilized a pool of previously undetectable Aβ that accounted for over half of the total intracellular Aβ. Aβ1-42 was more abundant than Aβ1-40 in this pool, and most of the insoluble Aβ1-42 was generated in the endoplasmic reticulum/intermediate compartment pathway. High levels of insoluble Aβ were also detected in several nonneuronal cell lines engineered to overexpress the amyloid-β precursor protein. This insoluble intracellular pool of Aβ was exceptionally stable, and accumulated in NT2N neurons in a time-dependent manner, increasing 12-fold over a 7-wk period in culture. These novel findings suggest that Aβ amyloidogenesis may be initiated within living neurons rather than in the extracellular space. Thus, the data presented here require a reexamination of the prevailing view about the pathogenesis of Aβ deposition in the AD brain.

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Crossref · 10.1083/jcb.141.4.1031

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  • Subsequent work showed that particularly the disease-linked Aβ42 peptide, rather than the more abundantly secreted Aβ40 peptide, increased with differentiation and time in culture within clonal NT2 cells.

    “Subsequent work showed that particularly the disease-linked Aβ42 peptide, rather than the more abundantly secreted Aβ40 peptide, increased with differentiation and time in culture within clonal NT2 cells that can develop a neuron-like phenotype [174, 195].”

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Authors
Skovronsky, D. M., Doms, R. W., & Lee, V. M.-Y.
Affiliations
University of Pennsylvania (US)
Venue
The Journal of Cell Biology
Published
1998-05-18
Volume
141
Issue
4
Pages
1031-1039
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
OpenAlex
W2130792655
Cited by
290
References
36
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 3 · 2019: 8 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 6 · 2014: 3 · 2013: 8 · 2012: 8
FWCI
15.16
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
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, amyloid-beta 42, Aβ40, endoplasmic reticulum, amyloidogenesis, Alzheimer's disease, amyloid plaques, amyloid precursor protein overexpression, formic acid extraction
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Line, Endoplasmic Reticulum, Genetic Vectors, Cricetinae, Humans, Neurons, Peptide Fragments, Recombinant Proteins, Semliki forest virus, Solubility, Subcellular Fractions, Transfection, Tumor Cells, Cultured, Amyloid beta-Peptides, CHO Cells, Carcinoma, Embryonal

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