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Cited by 57Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Synaptic and Endosomal Localization of Active γ-Secretase in Rat Brain

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Frykman, Susanne, Hur, Ji-Yeun, Frånberg, Jenny, Aoki, Mikio, Winblad, Bengt, Nahalkova, Jarmila, Behbahani, Homira, Tjernberg, Lars O.·2010·PLoS ONE
DOI 10.1371/journal.pone.0008948PMC PMC2812513
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Abstract

BACKGROUND: A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (Abeta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain. PRINCIPAL FINDINGS: We show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of Abeta40, is present in an endosome- and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high Abeta40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy. SIGNIFICANCE: The information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.

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  • The endogenous mature γ-secretase is situated in the TGN and/or the endosomal pathway.

    “Different studies have analyzed the location of the endogenous mature γ-secretase, concluding that it is situated in the TGN and/or the endosomal pathway.”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [69]

  • A membrane fraction enriched in syntaxin 13 has more γ-secretase activity in rat brain extracts.

    “Hence, it was also determined that a membrane fraction enriched in syntaxin 13 has more γ-secretase activity in rat brain extracts [69].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [69]

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Cited by

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Authors
Frykman, S., Hur, J.-Y., Frånberg, J., Aoki, M., Winblad, B., Nahalkova, J., Behbahani, H., & Tjernberg, L. O.
Affiliations
Karolinska Institutet (SE)
Corresponding author
Frykman, Susanne
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-01-28
Volume
5
Issue
1
Pages
e8948
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0008948
PMC
PMC2812513
OpenAlex
W2015798402
Cited by
57
References
3
Citations by year
2026: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 7 · 2019: 1 · 2018: 1 · 2017: 6 · 2016: 4 · 2015: 2 · 2014: 10 · 2013: 6 · 2012: 6
FWCI
4.27
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Dainippon Sumitomo Pharma
  • Karolinska Institutet
  • National Institute of Neurological Disorders and Stroke (R01NS039287, R01NS038752)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
gamma-secretase, subcellular localization, synaptic vesicles, endosomes, amyloid-beta, Alzheimer's disease, presenilin, nicastrin, APH-1, Pen-2, synaptic membranes, rat brain
MeSH terms
Animals, Brain, Male, Microscopy, Electron, Endosomes, Synapses, Rats, Sprague-Dawley, Microscopy, Confocal, Rats, Amyloid Precursor Protein Secretases

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