Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice

Abstract

Background The role of physical exercise in the prevention of Alzheimer’s disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear. Methods Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia. Results Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2′-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice. Conclusions Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.

Long-Term Cardiac Disease- and Cancer-Associated Mortalities in Patients With Non-Metastatic Stomach Adenocarcinoma Receiving Resection and Chemotherapy: A Large Competing-Risk Population-Based Cohort Study

“…To tackle this, systemic chemotherapy has been additionally recommended for resected patients who are in good medical condition to receive other treatment, and has contributed to further enhanced survival [ 32 ]; however, the survival improvement appears small, and not every patient with resected gastric cancer benefits from additional systemic treatment [ 13 - 16 ]. Outstandingly, the chemotherapy-induced cardiotoxicity is increasingly causing concern and may compete with the underlying cancer as a major cause of mortality, especially in older patients more often with basic heart diseases as comorbidity [ 18 - 22 ]. A retrospective study reports that cardiotoxicity occurs in 30% of gastric cancer patients managed with fluorouracil-based chemotherapy, where 10% experienced toxicity greater than grade 2 and 2% eventually died [ 18 ].…”

“…Outstandingly, the chemotherapy-induced cardiotoxicity is increasingly causing concern and may compete with the underlying cancer as a major cause of mortality, especially in older patients more often with basic heart diseases as comorbidity [ 18 - 22 ]. A retrospective study reports that cardiotoxicity occurs in 30% of gastric cancer patients managed with fluorouracil-based chemotherapy, where 10% experienced toxicity greater than grade 2 and 2% eventually died [ 18 ]. Accordingly, we found that heart diseases were the most common non-cancer cause of death in patients with nmGaC.…”

“…While overall the application of chemotherapy has contributed to improvement of survival in some patients with resected nmGaC throughout the last decades, not all patients benefit from chemotherapy use [ 13 - 16 ], and the long-term mortality due to persistent deterioration in left ventricular ejection fraction and incidental heart diseases remains a major threat to cancer survivors [ 17 ]. The commonly used chemotherapeutic agents for nmGaC include fluorouracil-based (e.g., capecitabine, 5-fluorouracil, S-1, and tegafur) and platinum-based drugs (e.g., oxaliplatin and cisplatin); and their potential cardiotoxicity has long attracted oncologists’ attention [ 18 - 22 ]. On the other hand, to receive further chemotherapy after resection, patients usually undergo careful assessment and selection based on performance status and others, and can be generally medically fitter and more tolerable than overall resected patients.…”

The Association of CSF sTREM2 With Cognitive Decline and Its Dynamic Change in Parkinson's Disease: Analysis of the PPMI Cohort

“…On the other hand, sTREM2 promoted proinflammatory responses of microglia via PI3K-NF-κB pathway and triggers inflammatory cytokine release, which may cause neuronal death (Zhong et al, 2017 ; Hickman et al, 2018 ). Additionally, inhibiting shedding and releasing of TREM2 and maintaining protein levels in TREM2 improved cognitive function in APP/PS1 mice, suggesting that TREM2, but not sTREM2, has a protective effect against inflammation and neuronal damage (Zhang et al, 2022 ). These findings further support that CSF sTREM2 may be a potential biomarker of TREM2-mediated microglia function and neuronal injury.…”

Trem2 deficiency does not worsen metabolic function in diet-induced obese mice

“…Nonetheless, given that metabolic function (i.e., glucose and lipid metabolism) is not adversely affected by loss of Trem2 in the present study, it seems unlikely that peripheral metabolic adaptations to exercise training would require Trem2. In addition, in the absence of disease (controls used in rodent Alzheimer's models (10,24)), exercise does not further enhance Trem2 expression, suggesting that exercise may prevent the suppression of Trem2 expression following microglia activation, but exercise does not seem to increase Trem2 expression above basal. It may be that exercise motivation or recovery to muscle damage (i.e., mild injury) are influenced by Trem2 expression.…”