8im7
Human gamma-secretase treated with ganglioside GM1
Structural highlights
DiseaseNICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. FunctionNICA_HUMAN Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. Publication Abstract from PubMedA hallmark of Alzheimer's disease (AD) is the senile plaque, which contains beta-amyloid peptides (Abeta). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Abeta processing is rarely known. Abeta levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of gamma-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of gamma-secretase structure and specifically accelerates gamma-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Abeta generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of gamma-secretase activity and the pathogenesis of AD. Preferential Regulation of Gamma-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.,Wang X, Zhou R, Sun X, Li J, Wang J, Yue W, Wang L, Liu H, Shi Y, Zhang D Adv Sci (Weinh). 2023 Nov;10(32):e2303411. doi: 10.1002/advs.202303411. Epub 2023 , Sep 27. PMID:37759382[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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