Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer β-amyloid peptides
Open accessAbstract
The excessive generation and accumulation of 40- and 42-aa β-amyloid peptides (Aβ 40 /Aβ 42 ) in selectively vulnerable brain regions is a major neuropathological feature of Alzheimer’s disease. Aβ, derived by proteolytic cleavage from the β-amyloid precursor protein (βAPP), is normally secreted. However, recent evidence suggests that significant levels of Aβ also may remain inside cells. Here, we have investigated the subcellular compartments within which distinct amyloid species are generated and the compartments from which they are secreted. Three experimental approaches were used: ( i ) immunofluorescence performed in intact cortical neurons; ( ii ) sucrose gradient fractionation performed with mouse neuroblastoma cells stably expressing wild-type βAPP 695 (N2a 695 ); and ( iii ) cell-free reconstitution of Aβ generation and trafficking from N2a 695 cells. These studies demonstrate that: ( i ) Aβ 40 (Aβ 1–40 plus Aβ x-40 , where x is an NH 2 -terminal truncation) is generated exclusively within the trans-Golgi Network (TGN) and packaged into post-TGN secretory vesicles; ( ii ) Aβ x-42 is made and retained within the endoplasmic reticulum in an insoluble state; ( iii ) Aβ 42 (Aβ 1–42 plus Aβ x-42 ) is made in the TGN and packaged into secretory vesicles; and ( iv ) the amyloid peptides formed in the TGN consist of two pools (a soluble population extractable with detergents and a detergent-insoluble form). The identification of the organelles in which distinct forms of Aβ are generated and from which they are secreted should facilitate the identification of the proteolytic enzymes responsible for their formation.
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The generation of Aβ42 in the ER might preclude it from translocating to the mitochondria.
“the generation of Aβ42 in the ER (50) might preclude it from translocating to the mitochondria.”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [50]
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- Authors
- Greenfield, J. P., Tsai, J., Gouras, G. K., Hai, B., Thinakaran, G., Checler, F., Sisodia, S. S., Greengard, P., & Xu, H.
- Affiliations
- Cornell University (US)
- Laboratory of Molecular and Cellular Neuroscience, and Fisher Center for Research on Alzheimer Disease, The Rockefeller University, 1230 York Avenue, New York, NY 10021; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021; Institute de Pharmacologie Moleculaire et Cellulaire, 06560 Valbonne, France; and Department of Pharmacological and Physiological Science, University of Chicago, 947 East 58th Street, Chicago, IL 60637
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-01-19
- Volume
- 96
- Issue
- 2
- Pages
- 742-747
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC15207
- OpenAlex
- W1975775468
- Cited by
- 366
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 15 · 2021: 5 · 2020: 11 · 2019: 12 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 18 · 2014: 9 · 2013: 17 · 2012: 20
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute on Aging (AG09464, P01AG009464)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, Alzheimer's disease, endoplasmic reticulum, trans-Golgi network, Aβ40, amyloid-beta 42, amyloid precursor protein, intracellular trafficking, secretory vesicles, cortical neurons, proteolytic cleavage
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Fractionation, Cells, Cultured, Centrifugation, Density Gradient, Endoplasmic Reticulum, Golgi Apparatus, Humans, Immunohistochemistry, Microscopy, Fluorescence, Peptide Fragments, Amyloid beta-Peptides, Rats
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