ArticleProceedings of the National Academy of Sciences of the United States of America2017
Bidirectional regulation of Aβ levels by Presenilin 1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration.Journal of neuroinflammation · 2023Review
- ProbioticNutrients · 2022Article
- The protein kinase CK1: Inhibition, activation, and possible allosteric modulation.Frontiers in molecular biosciences · 2022Review
- Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications.Journal of molecular evolution · 2020Article
- A Novel NIR-FRET Biosensor for Reporting PS/γ-Secretase Activity in Live Cells.Sensors (Basel, Switzerland) · 2020Article
- [Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2020Article
- Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer's disease.Alzheimer's research & therapy · 2020Article
- The Nuclear Lamina: Protein Accumulation and Disease.Biomedicines · 2020Review
- Article
- Exploring the bi-directional relationship between autophagy and Alzheimer's disease.CNS neuroscience & therapeutics · 2020Review
- Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death.Metabolic brain disease · 2020Review
- Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development.PloS one · 2020Article
- Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice.International journal of molecular sciences · 2019Article
- Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders.Pancreas · 2019Review
- Review
- Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- N-terminal Huntingtin (Htt) phosphorylation is a molecular switch regulating Htt aggregation, helical conformation, internalization, and nuclear targeting.The Journal of biological chemistry · 2018Article
- Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling.Cell death & disease · 2018Article
- Effects of ovarian hormone loss on neuritic plaques and autophagic flux in the brains of adult female APP/PS1 double-transgenic mice.Acta biochimica et biophysica Sinica · 2018Article
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7 authors at 2 institutions in 1 country.
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Abstract
Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aβ levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aβ levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aβ peptide and in βCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of βCTF, resulting in its accumulation and increased levels of Aβ peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aβ levels by increasing βCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates βCTF degradation may aid in the development of potential therapies for Alzheimer's disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.