ArticleProceedings of the National Academy of Sciences of the United States of America2022
Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.International journal of molecular sciences · 2026Review
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- NEK7 induces lactylation in Alzheimer's disease to promote pyroptosis in BV-2 cells.Molecular brain · 2024Article
- Liquid-liquid phase separation in Alzheimer's disease.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells.Nutrients · 2023Article
- Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides.ACS omega · 2023Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase is closely associated with Alzheimer’s disease (AD). γ-secretase activating protein (GSAP) specifically promotes γ-secretase–mediated cleavage of APP. However, the underlying mechanism remains enigmatic. Here, we demonstrate that the 16-kDa C-terminal fragment of GSAP (GSAP-16K) undergoes phase separation in vitro and forms puncta-like condensates in cells. GSAP-16K exerts dual modulation on γ-secretase cleavage; GSAP-16K in dilute phase increases APP–C-terminal 99-residue fragment (C99) cleavage toward preferred production of β-amyloid peptide 42 (Aβ42), but GSAP-16K condensates reduce APP-C99 cleavage through substrate sequestration. Notably, the Aβ42/Aβ40 ratio is markedly elevated with increasing concentrations of GSAP-16K. GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings mechanistically explain GSAP-mediated modulation of γ-secretase activity that may have ramifications on the development of potential therapeutics.
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Registered trials
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.