ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Dysregulation of hypoxia-inducible factor by presenilin/γ-secretase loss-of-function mutations.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 21 citations in OpenAlex.
- Potential Roles of Hypoxia-Inducible Factor-1 in Alzheimer's Disease: Beneficial or Detrimental?Antioxidants (Basel, Switzerland) · 2024Review
- Genetic Signatures of Positive Selection in Human Populations Adapted to High Altitude in Papua New Guinea.Genome biology and evolution · 2024Article
- Notch is Not Involved in Physioxia-Mediated Stem Cell Maintenance in Midbrain Neural Stem Cells.International journal of stem cells · 2023Article
- Cognitive decline in diabetic mice predisposed to Alzheimer's disease is greater than in wild type.Life science alliance · 2023Article
- Microvascular Contributions to Alzheimer Disease Pathogenesis: Is Alzheimer Disease Primarily an Endotheliopathy?Biomolecules · 2023Review
- The Potential of Ferroptosis-Targeting Therapies for Alzheimer's Disease: From Mechanism to Transcriptomic Analysis.Frontiers in aging neuroscience · 2021Review
- Emerging Roles of Inhibitor of Differentiation-1 in Alzheimer's Disease: Cell Cycle Reentry and Beyond.Cells · 2020Review
- Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease.International journal of molecular sciences · 2018Review
- Oxygen-dependent regulation of aquaporin-3 expression.Hypoxia (Auckland, N.Z.) · 2016Article
- The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin.Neurobiology of disease · 2015Review
- Destruction of a distal hypoxia response element abolishes trans-activation of the PAG1 gene mediated by HIF-independent chromatin looping.Nucleic acids research · 2015Article
- Induction of long noncoding RNA MALAT1 in hypoxic mice.Hypoxia (Auckland, N.Z.) · 2015Article
- Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism.Frontiers in neuroscience · 2015Article
- Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.Cell reports · 2014Article
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Presenilin (PSEN) 1 and 2 are the catalytic components of the γ-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid β that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia-inducible factors (HIFs), the master regulators of the hypoxic response. We previously identified the FK506 binding protein 38 (FKBP38) as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain-specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1α protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic γ-secretase function of PSEN1/2 was needed for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxic response, involving the generation of AICD. Together, our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade.
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