REVIEW article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1637671
This article is part of the Research TopicMolecular mechanisms of neurodegenerationView all 19 articles
The Manipulator Behind "Scissors": γ-Secretase and Its Modulators in Alzheimer's Disease
Provisionally accepted
Ning Gao1,2*
Fan Xing1,3
Juan Du1,4Wenxue Zhao1,4Sijia Wang1,4Meinei Chen1,4Xiaolong Dong1,4Yiming Qi1,4- 1Yan'an University, Yan'an, China
- 2Yan‘an medical school of Yan'an university, Yan‘an, China
- 3Yan'an medical school of Yan'an university, Yan'an, China
- 4Medical College of Yan'an University, Yan'an, China
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The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to "molecular scissors" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.
Keywords: γ-secretase, Alzheimer's disease, GSMS, GSMPs, Type I transmembrane protein
Received: 29 May 2025; Accepted: 08 Aug 2025.
Copyright: © 2025 Gao, Xing, Du, Zhao, Wang, Chen, Dong and Qi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ning Gao, Yan'an University, Yan'an, China
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