Preferential Regulation of Γ-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease

A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains beta-amyloid peptides (A beta). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating A beta processing is rarely known. A beta 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 A beta 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.

Automated summary

This study reveals the mechanism of GM1 in Aβ generation and provides evidence that decreasing GM1 levels represents a potential strategy in AD treatment. GM1 can lead to conformational change in the structure of γ-secretase and accelerate the cleavage of APP, leading to reduced plaque deposition and improved cognitive dysfunction in AD.