Near-Infrared Imaging of Senescence-Associated -Galactosidase Enables Discovery of a Glycerol-3-Phosphate Dehydrogenase 2-Regulated Neuroprotective Pathway in Alzheimers Disease

发布时间：2026-08-26 发布者： 浏览次数：5

Journal: ACS SensorsManuscript No.: se-2026-02748t (10.1021/acssensors.6c02748)Title: Near-Infrared Imaging of Senescence-Associated -Galactosidase Enables Discovery of a Glycerol-3-Phosphate Dehydrogenase 2-Regulated Neuroprotective Pathway in Alzheimers DiseaseAuthors: chuanhao Xu, Haoyi Liang, Yongjia Chen, Xunkai Wang, Govindaraj Tamil Selvan, Keyu Wang, Qikai Zhu, Yanlong Xing, Kun Dou, Fabiao Yu, Jiao Lu .

ACS Sens. (2026)

https://doi.org/10.1021/acssensors.6c02748

Abstract

Neuronal senescence is increasingly recognized as a contributor to Alzheimer's disease (AD), yet the molecular mechanisms underlying its progression remain incompletely understood. Herein, we introduce XCH-sen, a β-galactosidase (β-Gal)-responsive near-infrared fluorescent probe designed for imaging senescence-associated β-Gal activity in living cells and animals. Utilizing XCH-sen, we identified glycerol-3-phosphate dehydrogenase 2 (GPD2) as a previously unrecognized regulator of neuronal senescence. The deficiency of GPD2 significantly increased β-Gal activity and accelerated neuronal senescence, which was consistent with the results of SA-β-Gal staining. Mechanistically, loss of GPD2 disrupts mitochondrial redox homeostasis, leading to oxidative stress, mitochondrial dysfunction, impaired autophagic flux, and inflammatory activation, which collectively drive activation of the P16/P21/P53 pathway and cell-cycle arrest. In vivo, GPD2 deficiency exacerbates cognitive impairment, neuroinflammation, Aβ accumulation, and neuronal damage in AD models. Together, this work identifies GPD2 as a metabolic regulator of neuronal senescence and demonstrates the utility of molecular imaging in uncovering mechanisms underlying the progression of neurodegenerative diseases.

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