OBJECTIVE: The impairment of cognitive function has been associated with Alzheimer's disease (AD). Exercise exerts a positive modulatory effect on cognition by reducing synapse injury. However, limited in vivo evidence is available to validate the neuroprotective effect of TREM2 on synaptic function in this phenomenon. Here, we aim to explore whether physical exercise pretreatment alters Aβ-induced recognition memory impairment in structural synaptic plasticity within the hippocampus in AD rats. METHODS：: In study 1, fifty-two Sprague-Dawley (SD) rats were randomly divided into following four groups: control group (C group, n = 13), Alzheimer's disease group (AD group, n = 13), 4 weeks of physical exercise and Alzheimer's disease group (Exe+AD group, n = 13), 4 weeks of physical exercise and blank group (Exercise group, n = 13). Four weeks of treadmill exercise intervention was performed, and AD model were established by intra-cerebroventricular injection (ICV) injection of Aβ RESULTS: Novel recognition index in novel object recognition test significantly decreased, and western blot demonstrate that hippocampal TREM2 protein is significantly decreased (P <
0.001). But physical exercise reversed this phenomenon(P <
0.001). In addition, compared with Con group, the neuron from Exe+AD group exhibited a more complex branching pattern (P <
0.05). And impaired synaptic ultrastructure was observed in AD group. Hippocampal synaptic-related protein (SYX, SYP, GAP43, PSD95) and neurotransmitter (DA, Glu, GABA) was also significantly decreased (P <
0.01) in AD group. But the neuroprotection effect can be found in Exe+AD group, which are associated with the inhibition of synaptic injury by activate hippocampal TREM2 (P <
0.05). However, when blockade of hippocampal TREM2 reduced brain protective effect of exercise in AD rat model, including increased the damage of neuronal dendritic complexity, synaptic ultrastructure, and the decrease of hippocampal synapses-related protein, typical neurotransmitter. CONCLUSION: Treadmill exercise facilitated recognition memory acquisition via TREM2-mediated structural synaptic plasticity of the hippocampus in an AD rat model.