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Secreted β-Amyloid Precursor Protein Counteracts the Proapoptotic Action of Mutant Presenilin-1 by Activation of NF-κB and Stabilization of Calcium Homeostasis
Open accessAbstract
Mutations in the presenilin-1 (PS-1) gene account for approximately 50% of the cases of autosomal dominant, early onset, inherited forms of Alzheimer's disease (AD). PS-1 is an integral membrane protein expressed in neurons and is localized primarily in the endoplasmic reticulum (ER). PS-1 mutations may promote neuronal degeneration by altering the processing of the beta-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid beta-peptide (Abeta) and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPPalpha). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPPalpha activated the transcription factor NF-kappaB and prevented apoptosis induced by Abeta. Treatment of cells with kappaB decoy DNA blocked the antiapoptotic action of sAPPalpha, demonstrating the requirement for NF-kappaB activation in the cytoprotective action of sAPPalpha. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-kappaB activity following exposure to Abeta, which was characterized by enhanced early activation of NF-kappaB followed by a prolonged depression of activity. Blockade of NF-kappaB activity in cells expressing mutant PS-1 by kappaB decoy DNA was associated with enhanced Abeta-induced increases of [Ca2+]i and mitochondrial dysfunction. Treatment of cells with sAPPalpha stabilized [Ca2+]i and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-kappaB. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigargin induced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal role for ER calcium release in the proapoptotic action of mutant PS-1. Finally, a role for NF-kappaB in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPPalpha prevents thapsigargin-induced apoptosis, an effect blocked by kappaB decoy DNA. We conclude that sAPPalpha stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappaB. The data further suggest that PS-1 mutations result in aberrant NF-kappaB regulation that may render neurons vulnerable to apoptosis.
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“These analyses indicated significant Aβ42-mediated upregulation in the expression of a family of genes encoding the cytokines IL-1β, CEX-1, and TNF-α, COX-2, B94, and the proapoptotic Bax and Bik proteins (Guo et al., 1998; Metcalfe et al., 2004; Tarte et al., 2004).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Guo et al., 1998
In the citing paper
“The amyloid plaque of AD shows Aβ40/Aβ42 enriched ratio (Guo et al., 1998; Selkoe and Kopan, 2003)”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Guo et al., 1998
In the citing paper
“sAPPα promotes neuritogenesis and long-term survival of neurons in culture and protects brain cells against the toxicity of Aβ40 and Aβ42 peptides and excitotoxic and ischemic injury both in cell cultures and in vivo (Guo et al., 1998; Stein and Johnson, 2003).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Guo et al., 1998
In the citing paper
“sAPPα also protect neural cells against the proapoptotic thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, and the adverse effect of thapsigargin can be abolished in cells overexpressing antiapoptotic Bcl-2 (Guo et al., 1998).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Guo et al., 1998
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“Furthermore, NPD1 biosynthesis is enhanced by the neurotrophic peptide sAPPα, a 612-amino acid fragment derived from α-secretase-mediated cleavage of βAPP (Guo et al., 1998; Selkoe and Kopan, 2003).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Guo et al., 1998
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Self-citationThe Role of Presenilins in Aβ-Induced Cell Death in Alzheimer’s Disease
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Mattson, M. (1999) · doi:10.1002/(sici)1097-4547(19991001)58:1
Self-citation
Metadata
- Authors
- Guo, Q., Robinson, N., & Mattson, M. P.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Mattson, Mark P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-05
- Volume
- 273
- Issue
- 20
- Pages
- 12341-12351
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2055585878
- Cited by
- 196
- References
- 85
- Citations by year
- 2026: 2 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 1 · 2013: 5 · 2012: 5
- FWCI
- 13.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag014554-07, 5r01ns035253-03, NS35253, AG05144, AG14554)
- National Institute on Aging (P50AG005144, AG14554, AG-05144)
- National Institute of Neurological Disorders and Stroke (NS 35253)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- presenilin 1, amyloid precursor protein, sAPPα, NF-κB, apoptosis, Alzheimer's disease, calcium homeostasis, endoplasmic reticulum calcium release, thapsigargin, mitochondrial dysfunction, oxidative stress, amyloid-beta, PC12 cells
- MeSH terms
- Animals, Calcium, Homeostasis, Humans, Membrane Proteins, Mutation, Amyloid beta-Peptides, NF-kappa B, Amyloid beta-Protein Precursor, PC12 Cells, Apoptosis, Rats, Presenilin-1
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