Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

Busciglio, J; Gabuzda, D H; Matsudaira, P; Yankner, B A

doi:10.1073/pnas.90.5.2092

Cited by 569Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

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Busciglio, J, Gabuzda, D H, Matsudaira, P, Yankner, B A·1993·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.90.5.2092PMC PMC46027

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Abstract

The cellular mechanism underlying the generation of beta-amyloid in Alzheimer disease and its relationship to the normal metabolism of the amyloid precursor protein are unknown. In this report, we show that 3- and 4-kDa peptides derived from amyloid precursor protein are normally secreted. Epitope mapping and radiolabel sequence analysis suggest that the 4-kDa peptide is closely related to full-length beta-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the beta-amyloid N terminus. The beta-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of beta-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of beta-amyloid-related peptides occurs in a wide variety of cell types, but which peptides are produced and their absolute levels are dependent on cell type. Human astrocytes generated higher levels of beta-amyloid than any other cell type examined. These results suggest that beta-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of beta-amyloid production in the brain.

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APP mutations occurring near the β-secretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ.
“mutations occurring near the βsecretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ [34, 35].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [34]

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Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921 · see citing works
Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schiossmacher, M., Whaley, J., Swindlehurst, C., et al. (1992) · Nature · doi:10.1038/359325a0 · Cited by 1,731 · see citing works
Production of the Alzheimer Amyloid β Protein by Normal Proteolytic Processing
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X.-D., McKay, D. M., Tintner, R., Frangione, B., et al. (1992) · Science · doi:10.1126/science.1439760 · Cited by 1,447 · see citing works

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Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
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Reaume, A. G., Howland, D. S., Trusko, S. P., Savage, M. J., Lang, D. M., Greenberg, B. D., Siman, R., & Scott, R. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.38.23380 · Cited by 150 · see citing works
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“For example, mutations occurring near the β-secretase cleavage site, such as the Swedish mutation (K670N/ M671L), appear to result in increased production of total Aβ (Busciglio et al., 1993; Citron et al., 1994).”
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Troncoso, J. C., Cataldo, A. M., Nixon, R. A., Barnett, J. L., Lee, M. K., Checler, F., Fowler, D. R., Smialek, J. E., Crain, B., Martin, L. J., et al. (1998) · Annals of Neurology · doi:10.1002/ana.410430519 · Cited by 93 · see citing works
Altered cleavage and secretion of a recombinant β–APP bearing the Swedish familial Alzheimer's disease mutation
Felsenstein, K. M., Hunihan, L. W., & Roberts, S. B. (1994) · Nature Genetics · doi:10.1038/ng0394-251 · Cited by 90 · see citing works
Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25–35 in human cortical astrocytes and neurons—Therapeutic relevance to Alzheimer's disease
Armato, U., Chiarini, A., Chakravarthy, B., Chioffi, F., Pacchiana, R., Colarusso, E., Whitfield, J. F., & Dal Prà, I. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.04.020 · Cited by 68 · see citing works
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Chiarini, A., Armato, U., Liu, D., & Dal Prà, I. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00134 · Cited by 51 · see citing works
Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant
Levy, E., Prelli, F., & Frangione, B. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s337 · Cited by 24 · see citing works
A new brain metalloendopeptidase which degrades the Alzheimer ß-amyloid 1-40 peptide producing soluble fragments without neurotoxic effects
Carvalho, K. M., França, M. S. F., Camarão, G. C., & Ruchon, A. F. (1997) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x1997001000002 · Cited by 11 · see citing works

Authors: Busciglio, J., Gabuzda, D. H., Matsudaira, P., & Yankner, B. A.
Affiliations: Harvard University (US)
ORCID: Busciglio, J
Gabuzda, D H
Matsudaira, P
Yankner, B A
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1993-03
Volume: 90
Issue: 5
Pages: 2092-2096
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.90.5.2092
PMC: PMC46027
OpenAlex: W1984996311
Cited by: 569
References: 4
Citations by year: 2026: 5 · 2025: 8 · 2024: 9 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 14 · 2016: 18 · 2015: 2 · 2014: 5 · 2013: 8 · 2012: 5
FWCI: 40.44
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association
American Federation for Aging Research
National Institutes of Health (5r29ag009229-05)
National Institute on Aging (AG09229)
National Institute of Neurological Disorders and Stroke (R01NS030352, NS30352)
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 precursor protein, Alzheimer's disease, secretory pathway, Golgi apparatus, protein secretion, astrocytes, glial cells, neurons, lysosomal inhibitors, epitope mapping
MeSH terms: Amino Acid Sequence, Animals, Astrocytes, Cells, Cultured, Chlorocebus aethiops, Golgi Apparatus, Lysosomes, Molecular Sequence Data, Neurons, Peptide Fragments, Recombinant Proteins, Solubility, Time Factors, Transfection, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, In Vitro Techniques

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Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

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