AUTHOR=Wang Yi-Jie , Wang Yu-Xin , Zou Cheng-Zhi , Zhang Wei-Jun , Pan Wen , Wang Jia-Qing , Wang Hua , Qian Xin , Han Guo-Jia-Hao , Liu Feng-Guo , Wang Jia 

TITLE=PGC-1α promotes the survival of newborn neurons within AD hippocampus through activation of the FNDC5/BDNF/TrkB signaling pathway

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 18 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2025.1688694

DOI=10.3389/fnmol.2025.1688694

ISSN=1662-5099

ABSTRACT=BackgroundThe learning and memory impairments observed in Alzheimer’s disease (AD) are strongly associated with impaired neurogenesis in the hippocampal region. Our previous research has highlighted the potential of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in ameliorating AD-related pathological changes. As a key metabolic regulator, PGC-1α is highly expressed in energy-demanding tissues such as the hippocampus. However, its specific roles and underlying mechanisms in AD-associated neurogenesis remains largely unclear.ObjectiveThis study aimed to elucidate the precise role and molecular mechanisms by which PGC-1α regulates the survival of newly generated neurons during neurogenesis in the AD-affected hippocampus.MethodsUsing combined models of PGC-1α overexpression in the hippocampal dentate gyrus (DG) of AD-model mice and PGC-1α knockout mice, we investigated the effects of gain- and loss-of-function of PGC-1α on the regulation of the FNDC5/BDNF/TrkB signaling pathway, as well as on the survival of newborn neurons in the AD-affected hippocampus.ResultsOur findings demonstrate that PGC-1α enhances the survival of newly generated neurons in the AD-affected hippocampus. Furthermore, PGC-1α functions acts as an upstream regulator of the FNDC5/BDNF/TrkB signaling pathway, and its knockdown suppresses neuronal survival by inhibiting this pathway.ConclusionThese results indicate that PGC-1α serves as a critical mediator in the FNDC5/BDNF/TrkB signaling pathway within newborn neurons. Enhancing PGC-1α expression, either pharmacologically or through alternative approaches, may therefore represent a promising therapeutic strategy for Alzheimer’s disease.