Author(s): WANG, C., Institution: HARBIN SPORT UNIVERSITY, Country: CHINA, Abstract-ID: 1260

INTRODUCTION:
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder, and cerebral glucose metabolism dysfunction may be its initiating factor. The locus coeruleus-hippocampal noradrenergic neural circuit (LC→HPC-NE) plays a crucial role in maintaining neuronal function and memory formation. This study aimed to determine whether moderate-intensity aerobic exercise improves cognitive impairment in APP/PS1 double-transgenic AD model mice by activating the LC→HPC-NE neural circuit and to reveal its related mechanisms.​
METHODS:
Thirty 16-week-old SPF-grade male APP/PS1 mice and 10 age-matched male C57BL/6J mice were selected. The APP/PS1 mice were randomly divided into the AD group, AD aerobic exercise group (Sport group), and AD aerobic exercise + DSP-4 group (DSP4 group), with C57BL/6J mice as the control group. The Sport group and DSP4 group received 12 weeks of moderate-intensity treadmill training, and the DSP4 group was simultaneously injected with DSP-4 to damage the LC→HPC-NE pathway. Behavioral tests (novel object recognition, Y-maze, water maze) were used to evaluate cognitive function. Combined with resting-state magnetic resonance imaging, neural circuit tracing, fiber photometry recording, histopathology and molecular biology methods, indicators such as brain structure and function, neural circuit activity, neuronal morphology and Aβ deposition were detected.​
RESULTS:
Behavioral results showed that compared with the control group, the cognitive function of mice in the AD group was significantly impaired, while the cognitive impairment in the Sport group was significantly improved, and the DSP4 group offset the protective effect of exercise. Histopathological and molecular biological detection indicated that in the Sport group, hippocampal neuronal degeneration was reduced, the number of Nissl bodies was increased, the density of dendritic spines was elevated, and Aβ deposition was significantly decreased. Resting-state magnetic resonance imaging showed that the gray matter volume and neural activity intensity of brain regions such as the hippocampus and locus coeruleus in the Sport group were significantly increased. Fiber photometry recording and circuit tracing confirmed that the Ca2+ signal intensity of the LC→HPC-NE neural circuit in the Sport group was significantly enhanced, while the circuit activity in the DSP4 group continued to decrease.​
CONCLUSION:
Moderate-intensity aerobic exercise can effectively improve cognitive impairment in APP/PS1 mice, and its mechanism is closely related to activating the LC→HPC-NE neural circuit, enhancing the neuronal activity of this circuit, thereby improving hippocampal neuronal synaptic plasticity, reducing Aβ deposition, and protecting brain structure and function. The LC→HPC-NE neural circuit may be a key mediating pathway for moderate-intensity aerobic exercise to improve AD cognitive impairment, providing a theoretical basis for exercise intervention strategies for AD.