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.

Oral niacinamide mononucleotide (NMN) and aerobic exercise have been shown to enhance niacinamide adenine dinucleotide (NAD⁺) in the body. NAD⁺ plays a critical role in the body and can directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging, and immune cell function. It is noteworthy that the level of NAD⁺ decreases gradually with increasing age. Decreased levels of NAD⁺ have been causally associated with a number of diseases associated with aging, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many diseases related to aging can be slowed down or even reversed by restoring NAD⁺ levels. For example, oral NMN or exercise to increase NAD⁺ levels in APP/PS1 mice have been proven to improve mitochondrial autophagy, but currently, there is no regimen combining oral NMN with exercise. This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD⁺ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD⁺ level; (2) how exercise regulates the content of NAD⁺ in the body; (3) the relationship between exercise activation of NAD⁺ and AMPK; (4) how SIRT1 is regulated by NAD⁺ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD⁺ in vivo, we can infer how exercise elevates the level of NAD⁺ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer’s disease (AD).

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.