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

TL;DR

This study shows that PGC-1α helps new neurons survive in the brains of Alzheimer's patients by activating a specific signaling pathway.

Contribution

The study identifies PGC-1α as a key regulator of neuronal survival in AD through the FNDC5/BDNF/TrkB pathway.

Findings

PGC-1α enhances the survival of newborn neurons in the AD-affected hippocampus.

PGC-1α acts as an upstream regulator of the FNDC5/BDNF/TrkB signaling pathway.

Knockdown of PGC-1α suppresses neuronal survival by inhibiting this pathway.

Abstract

The 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.

This 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.

Using 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.

Our 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.

These 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.

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