A106: Aerobic Exercise Modulates GPCR/cAMP/PKA Signaling Pathway and Complement-Microglia Axis to Prevent Synaptic Loss in APP/PS1 Mice

Purpose: Synaptic failure serves as a primary contributor to memory dysfunction in Alzheimer\u27s disease (AD). Physical exercise has demonstrated the potential to thwart and delay degenerative alterations in memory functions linked to AD. Investigating the underlying mechanisms may unveil crucial insights into early pathological changes, offering breakthroughs for both understanding and treating AD. Methods: We utilized 3-month-old APP/PS1 mice and subjected them to a 12-week aerobic exercise intervention. The spatial learning and memory functions of the mice were assessed using the Morris water maze test, while Golgi staining was employed to determine dendritic spine density in each mouse group. To analyze the potential mechanisms mediating the effects of exercise intervention in the AD brain, we conducted RNA sequencing. Subsequently, pathway enrichment analysis, immunofluorescence, real-time quantitative PCR, and western blotting were employed to elucidate the impact of regular aerobic exercise on the GPCR/cAMP/PKA signaling pathway and complement-microglia axis. Results: Our findings reveal that a 12-week aerobic exercise intervention significantly enhanced spatial learning and memory function in APP/PS1 mice. Moreover, it led to a substantial increase in dendritic spine density and elevated expression of postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus. Aerobic exercise demonstrated the ability to improve the expression of certain genes and enhance synaptic pathways in the brains of APP/PS1 mice. This suggests that aerobic exercise facilitates synaptic growth in APP/PS1 mice by modulating G protein-coupled receptors (GPCRs) and activating the cAMP signaling pathway, with significant alterations observed in the expressions of Hcar1 and Vipr2 genes. Furthermore, exercise intervention resulted in the significant down-regulation (P \u3c 0.05 or P \u3c 0.01) of cAMP, p-PKA/PKA, GluA1, and CaMKII protein expressions in the brain tissue of APP/PS1 mice, which were subsequently up-regulated after exercise (P \u3c 0.01). Notably, regular aerobic exercise effectively suppressed the activation of IBA-1+ microglia cells (P \u3c 0.01), reversed changes in M1 phenotype markers (Cd86 and iNOS) and M2 phenotype markers (Arg-1) of microglia cells (P \u3c 0.05), reduced the production of promoters C1q and central factor C3 in the macrosomatic cascade (P \u3c 0.05), and prevented the colocalization of microglia and PSD-95 (P \u3c 0.01). Conclusion: In conclusion, our results indicate that physical exercise plays a pivotal role in fostering early synaptic growth and averting synaptic loss in Alzheimer\u27s disease (AD). This effect may be attributed to the regulation of the G protein-coupled receptors (GPCRs)/cAMP/PKA signaling pathway and the suppression of complement-mediated microglial phagocytosis of synapses. This mechanistic insight underscores the inherent contribution of exercise to health promotion, offering potential avenues for synaptic-focused interventions in the early stages of AD treatment

Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Abnormalities in autophagy are associated with Alzheimer’s disease (AD)-like lesions. Studies have shown that exercise can significantly improve AD autophagy abnormalities, but the mechanism underlying this phenomenon remains unclear. APN not only has an important regulatory effect on AD autophagy abnormalities, but also is affected by exercise. Therefore, this study aims to reveal the pathway by which exercise regulates abnormal autophagy in AD using the APN–AdipoR1 signaling pathway as an entry point. The results of the study showed that APP/PS1 double transgenic AD model mice (24 weeks) showed decreased AdipoR1 levels in the brain, abnormal autophagy, increased Aβ deposition, and increased cell apoptosis, and dendritic spines and cognitive function were reduced. Twelve weeks of aerobic exercise enhanced lysosomes and alleviated abnormal autophagy by activating the AdipoR1/AMPK/TFEB signaling pathway in the brains of AD mice, thereby alleviating Aβ deposition and its associated AD-like abnormalities. These findings suggest that the AdipoR1 plays an important role in aerobic exercise’s alleviation of abnormal autophagy in AD brain cells and alleviation of AD-like lesions

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer’s disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients

Treadmill Exercise Modulates Intestinal Microbes and Suppresses LPS Displacement to Alleviate Neuroinflammation in the Brains of APP/PS1 Mice

Neuroinflammation occurs throughout the pathogenesis of Alzheimer’s disease (AD). Here, we investigated the effects of treadmill exercise on neuroinflammation in APP/PS1 transgenic AD mice and the potential involvement of microbe–gut–brain axis (MGB) mechanisms based on growing evidence that AD’s pathogenesis is correlated with a deterioration in the function of gut microbiota. APP/PS1 transgenic AD mice were subjected to 12 weeks of treadmill exercise, followed by spatial memory tests. After the behavioral study, the amyloid (Aβ) pathology, gut microbes and metabolites, bacterial lipopolysaccharide (LPS) displacement, and degree of neuroinflammation were analyzed. We found that this strategy of exercise enriched gut microbial diversity and alleviated neuroinflammation in the brain. Notably, exercise led to reductions in pathogenic bacteria such as intestinal Allobaculum, increases in probiotic bacteria such as Akkermansia, increased levels of intestine–brain barrier proteins, and attenuated LPS displacement. These results suggest that prolonged exercise can effectively modulate gut microbes and the intestinal barrier and thereby reduce LPS displacement and ultimately alleviate AD-related neuroinflammation

A comparative study between limb-salvage and amputation for treating osteosarcoma

Purpose: Osteosarcoma is an aggressive malignant neoplasm, and conflicting findings have been reported on the survival and function recovery in osteosarcoma patients experiencing limb salvage or amputation. In the present study, we compared clinical outcomes regarding limb salvage surgery vs. amputation for osteosarcoma patients by a meta-analysis. Method: Literature search was conducted in CNKI, Medline, Embase, the Cochrane Database, and Web of Sciences, and the quality of included studies was evaluated based on Newcastle-Ottawa scale quality assessment. Odds ratio and 95% confidence interval of the local recurrence, 5-year overall survival, and metastasis occurrence were calculated. Results: 17 articles were included according to selection criteria. There were 1343 patients in total derived from these studies. Our result showed that there was no significant difference between limb salvage surgery and amputation with respect to local recurrence, and patients with limb salvage surgery had a higher 5-year overall survival, and a lower metastasis occurrence. Conclusions: The present study provided more comprehensive evidences to support limb salvage surgery as an optimal treatment of osteosarcoma patients