Recent studies have suggested that exercise may be beneficial for delaying or attenuating Alzheimer’s disease (AD). However, the underlying mechanisms were not clear. Microglia-mediated neuroinflammation is suggested to play an important role in the pathology of AD. The present study investigated the beneficial effects of treadmill exercise on amyloid-β (Aβ) deposition and cognitive function in amyloid precursor protein (APP)/PS1 mice in the early stage of AD progression and microglia-mediated neuroinflammation was mainly analyzed. The results demonstrated that 12 weeks of treadmill exercise preserved hippocampal cognitive function in APP/PS1 mice and substantially suppressed Aβ accumulation in the hippocampus. Treadmill exercise significantly inhibited neuroinflammation, which was characterized by a remarkably reduced expression of pro-inflammatory factors and increased expression of anti-inflammatory mediators in the hippocampus, resulting from a shift in activated microglia from the M1 to M2 phenotype. Treadmill exercise also attenuated oxidative stress presented by a marked reduction in methane dicarboxylic aldehyde (MDA) level and dramatically elevated SOD and Mn-SOD activities in the hippocampus. These findings suggest that treadmill exercise can effectively prevent the decrease in hippocampal-dependent cognitive function and Aβ deposits in early AD progression possibly
via
modulating microglia-mediated neuroinflammation and oxidative stress.
The β-amyloid (Aβ) deposition is one of the major pathological hallmark of Alzheimer’s disease. Dysfunction in autophagy has been reported to lead to the Aβ deposition. The current study aimed to investigate the effects of treadmill exercise on autophagy activity and the Aβ deposition and to demonstrate whether exercise-induced reduction in the Aβ deposition was associated with changes in autophagy activity. APP/PS1 transgenic mice were divided into transgenic sedentary (TG-SED, n=12) and transgenic exercise (TG-EXE, n=12) groups. Wild-type mice were also divided into sedentary (WT-SED, n=12) and exercise (WT-EXE, n=12) groups. The WT-EXE and TG-EXE mice were subjected to treadmill exercise for 12 weeks. The levels of Aβ plaques and soluble forms of Aβ, autophagy markers light chain 3 and P62, and lysosomal marker lysosome-associated membrane protein 1 (Lamp1) were measured in the hippocampus. Both Aβ plaques and soluble forms of Aβ (Aβ40 and Aβ42) were significantly increased in TG-SED mice compared with WT-SED mice, whereas exercise reduced Aβ deposition in APP/PS1 transgenic mice. Coincidentally, TG-SED mice displayed a decrease in autophagy activity as evidenced by a significant increase in the levels of light chain 3-II and P62, as well as an accumulation of lysosome as evidenced by a significant over-expression of Lamp1. Interestingly, exercise increased autophagy activity as evidenced by a significant reduction in the levels of P62 and Lamp1 in TG-EXE mice. These findings suggest that treadmill exercise is efficient in decreasing Aβ deposition by enhancing autophagy–lysosomal activity in APP/PS1 transgenic mice, demonstrating a possible approach in Alzheimer’s disease prevention and treatment.
Recent study has demonstrated that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have the same effect to alleviate β-amyloid pathology in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. Activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is pivotal and has been demonstrated to accelerate β-amyloid accumulation. The present study aimed to examine whether the exercise-induced β-amyloid reduction was associated with changes in NLRP3 inflammasome activation. APP/PS1 transgenic mice were randomly assigned to a transgenic sedentary group, HIIT group and MICT group. Nontransgenic littermates were used as wild-type sedentary group. Mice in HIIT and MICT groups were subjected to treadmill exercise for 12 weeks, 5 days/week. The results showed that compared with transgenic sedentary group, β-amyloid deposition in the hippocampus of HIIT and MICT groups were significantly reduced. Moreover, both HIIT and MICT groups displayed significant increases in the expression of microglial phagocytic receptors triggering receptor expressed on myeloid cells 2, CD36 and scavenger receptor class A compared with transgenic sedentary group. In addition, HIIT and MICT had the same effect to inhibit NLRP3 inflammasome activation, as evidenced by significant reduction in IL-1β, active caspase-1p20, NLRP3 and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain (ASC) levels as well as decreased NLRP3/ASC colocalization. These findings indicate that HIIT appears to be an effective intervention as MICT to reduced β-amyloid deposition by regulating NLRP3 inflammasome-controlled microglial phagocytosis.
Background: Cisplatin is an important agent in first-line chemotherapy against gastric cancer (GC). However, consequential drug resistance limits its effectiveness for the treatment of GC. Exosomes which are loaded with proteins, lipids and RNAs, have been proven to transfer malignant phenotype. This study aims to explore the role and mechanism of exosomal RPS3 protein in transmitting a chemoresistance phenotype from cisplatin resistant to cisplatin sensitive gastric cancer cells.Methods: A cisplatin resistant gastric cancer cell line SGC7901R was established by continuously grafting SGC7901S cells into cisplatin-containing culture medium. Exosomes from SGC7901R and SGC7901S were obtained and confirmed through ultracentrifuge and Nano Analyzer. By LC-MS/MS analysis methods, we detected the differentially expressed proteins in SGC7901R cells exosomes and SGC7901S cells exosomes. Western blotting was used to verify the differential expression of exosomal RPS3 between cisplatin resistant and parental cell lines. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of exosomal RPS3 protein in GC.Results: SGC7901R cell derived exosomes were readily taken up by cisplatin sensitive SGC7901S cells, thus triggering off a phenotype of chemoresistance in the receptor cells. Subsequently, it was demonstrated that exosomal RPS3 was essential for inducing chemoresistance of receptor cells as shown by the acquisition of this phenotype in SGC7901S cells with enforced expression of RPS3. Further mechanism study demonstrated that cisplatin‑resistant gastric cancer cells-derived exosomal RPS3 enhanced the chemoresistance of cisplatin‑sensitive gastric cancer cells through the PI3K-Akt-cofilin-1 signaling pathway.Conclusion: Cisplatin resistant gastric cancer cells communicate with sensitive cells through the intercellular delivery of exosomal RPS3 and activation of the PI3K-Akt-cofilin-1 signaling pathway. Targeting exosomal RPS3 protein in cisplatin resistant gastric cancer cells may thus be a promising strategy to overcome cisplatin resistance in gastric cancer.
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