Yarong Wang Rongxing Zhang Yumin Jiang Jingwen Liao Lianwei Mu ^* Min Hu ^*

• Guangzhou Sport University, Guangzhou, China

Anxiety and depression-like symptoms occur in the early stages of Alzheimer's disease. Hippocampal Sirtuin 1 (SIRT1) signaling mediates anxiety-and depression-like behavior. Exercise training improves anxiety and depression-like behavior in various disease models, such as the rat chronic restraint stress model, rat model of posttraumatic stress disorder, and rat model of fetal alcohol spectrum disorders. Here, we aimed to investigate whether exercise ameliorates anxiety-and depression-like behaviors in APP/PS1 mice and explore the potential mechanisms. We first observed that treadmill exercise improved anxiety-and depression-like behaviors in six-month-old APP/PS1 mice and increased SIRT1 levels in the hippocampus. Pharmacological activation of hippocampal SIRT1 function also reduced anxiety and depression-like behaviors in APP/PS1 mice. Meanwhile, both treadmill exercise and pharmacological activation of hippocampal SIRT1 increased the levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α), nuclear respiration factors 1 (NRF1), mitochondrial transcription factor A (TFAM), and enhanced mitochondrial biogenesis (CO2, ATP6, or mitochondrial content) in the hippocampus of APP/PS1 mice. These findings reveal that treadmill exercise reduces anxiety-and depression-like behaviors in six-monthold APP/PS1 mice by enhancing the SIRT1-dependent PGC-1 α /NRF1/TFAM axis, promoting mitochondrial biogenesis in the hippocampus.