PGC-1α Expands Neural Precursor Pool and Facilitates Cognitive Recovery Within AD Hippocampus Through the Regulation of Mitochondrial Dynamics.

The dysfunction in learning and memory observed in Alzheimer's disease (AD) is strongly associated with impaired neurogenesis in the hippocampal region. As research on adult neurogenesis advances, it becomes increasingly crucial to identify potential targets for interventions aimed at enhancing endogenous neurogenesis and promoting functional recovery in AD patients. Our previous studies have demonstrated the potential of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in mitigating the pathological abnormalities associated with AD. Serving as a ubiquitous metabolic regulator, PGC-1α is highly expressed in energy-demanding tissues, such as the hippocampus. However, the precise role and underlying mechanisms by which PGC-1α regulates neurogenesis within the AD-affected hippocampus remain to be fully elucidated. In this study, we induced PGC-1α overexpression by microinfusing AAV-Pgc-1α into the dentate gyrus (DG) of the hippocampus in APP/PS1 mice. Our findings indicate that PGC-1α effectively alleviates AD-related pathological abnormalities and behavioral dysfunction, including deficits in short-term habituation and spatial reference memory impairment. PGC-1α induces the activation of quiescent radial-glia like neural stem cells (NSCs) in the hippocampal DG region, giving rise to intermediate progenitor cells and neuroblasts that ultimately differentiate into mature neurons. By regulating mitochondrial dynamics-specifically promoting fusion while inhibiting fission-PGC-1α facilitates the expansion of precursor cell populations. Collectively, these findings highlight the significance of PGC-1α in maintaining NSC self-renewal, promoting neuronal lineage progression, and contributing to endogenous neurogenesis in AD. Elevating PGC-1α levels, either pharmacologically or through alternative approaches, may represent a promising therapeutic strategy for treating AD.