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Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria
Open accessAbstract
Mitochondria are central in the regulation of cell death. Apart from providing the cell with ATP, mitochondria also harbor several death factors that are released upon apoptotic stimuli. Alterations in mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected in Alzheimer's disease patients. These findings suggest that mitochondria may trigger the abnormal onset of neuronal cell death in Alzheimer's disease. We previously reported that presenilin 1 (PS1), which is often mutated in familial forms of Alzheimer's disease, is located in mitochondria and hypothesized that presenilin mutations may sensitize cells to apoptotic stimuli at the mitochondrial level. Presenilin forms an active gamma-secretase complex together with Nicastrin (NCT), APH-1, and PEN-2, which among other substrates cleaves the beta-amyloid precursor protein (beta-APP) generating the amyloid beta-peptide and the beta-APP intracellular domain. Here we have identified dual targeting sequences (for endoplasmic reticulum and mitochondria) in NCT and showed expression of NCT in mitochondria by immunoelectron microscopy. We also showed that NCT together with APH-1, PEN-2, and PS1 form a high molecular weight complex located in mitochondria. gamma-secretase activity in isolated mitochondria was demonstrated using C83 (alpha-secretase-cleaved C-terminal 83-residue beta-APP fragment from BD8 cells lacking presenilin and thus gamma-secretase activity) or recombinant C100-Flag (C-terminal 100-residue beta-APP fragment) as substrates. Both systems generated an APP intracellular domain, and the activity was inhibited by the gamma-secretase inhibitors l-685,458 or Compound E. This novel localization of NCT, PS1, APH-1, and PEN-2 expands the role and importance of gamma-secretase activity to mitochondria.
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“accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [65]
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Metadata
- Authors
- Hansson, C. A., Frykman, S., Farmery, M. R., Tjernberg, L. O., Nilsberth, C., Pursglove, S. E., Ito, A., Winblad, B., Cowburn, R. F., Thyberg, J., & Ankarcrona, M.
- Affiliations
- Karolinska Institutet (SE)
- The University of Sydney (AU)
- Corresponding author
- Ankarcrona, Maria
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 279
- Issue
- 49
- Pages
- 51654-51660
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2132814291
- Cited by
- 256
- References
- 41
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 12 · 2015: 7 · 2014: 10 · 2013: 12 · 2012: 22
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- gamma-secretase, mitochondria, nicastrin, presenilin 1, APH-1, Pen-2, Alzheimer's disease, amyloid precursor protein, APP intracellular domain, mitochondrial targeting sequence, neuronal apoptosis, gamma-secretase inhibitors, compound E
- MeSH terms
- Adenosine Triphosphate, Alzheimer Disease, Amino Acid Sequence, Animals, Brain, Cholic Acids, Detergents, Electrophoresis, Polyacrylamide Gel, Endoplasmic Reticulum, Golgi Apparatus, Male, Membrane Glycoproteins, Membrane Proteins, Mitochondria, Molecular Sequence Data, Neurons, Peptide Hydrolases, Endopeptidases, Peptides, Subcellular Fractions, Immunoblotting, Signal Transduction, Amyloid beta-Peptides, Microscopy, Immunoelectron, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Apoptosis, Protein Structure, Tertiary, Oxidative Stress, Immunoprecipitation, Rats, Presenilin-1, Amyloid Precursor Protein Secretases
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