Resistance Exercise Decreases Amyloid Load and Modulates Inflammatory Responses in the APP/PS1 Mouse Model for Alzheimer’s Disease

Hashiguchi, Debora; Campos, Henrique Correia; Wuo-Silva, Raphael; Faber, Jean; Silva, Sérgio Gomes da; Ribeiro, Antônio Augusto Coppi Maciel; Arida, Ricardo Mário; Longo, Beatriz M.

doi:10.3233/jad-190729

Cited by 34 publications

(24 citation statements)

References 65 publications

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“…Our study demonstrated that long-term voluntary physical exercise significantly reduces IL-6 levels in plasma and the cortex of WT and 5xFAD exercised mice, while IL-6 levels in muscle remain unchanged. Consistent with our findings, previous studies have shown that IL-6 is attenuated in the brain after treadmill exercise of healthy rats [22] and after resistance exercise in APP/PS1 mice [23]. Moreover, a recent human study demonstrated that aging induces increases in serum IL-6, while lifelong aerobic exercise during 50 years decreases serum IL-6 with no differences observed in skeletal muscle IL-6 levels [78].…”

Section: Discussionsupporting

confidence: 92%

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Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Belaya

Kucháriková

Górová

et al. 2021

IJMS

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Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.

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Section: Discussionsupporting

confidence: 92%

“…IL-6, a multifunctional cytokine that is paramount in immune responses and nervous system function, is increased in the brain during aging and AD [21]. In contrast, brain IL-6 levels are reduced upon regular physical exercise [22,23]. Exercise-induced IL-6 modulation remains poorly investigated in the context of AD.…”

Section: Introductionmentioning

confidence: 99%

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Belaya

Kucháriková

Górová

et al. 2021

IJMS

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“…Although research has focused on the effects of aerobic exercise (forced or voluntary exercise) in AD models (Nichol et al, 2007(Nichol et al, , 2008Xiong et al, 2015), less is known about the impact of resistance exercise on this pathology. Our group and others have recently shown that resistance exercise may minimize the alteration in exploratory activity (Hashiguchi et al, 2020) and in cognitive function (Liu et al, 2020) in a transgenic mouse model for AD.…”

Section: Physical Exercise In Adulthood Aging and Neurological Disordersmentioning

confidence: 97%

The Contribution of Physical Exercise to Brain Resilience

Arida

Teixeira-Machado

2021

Front. Behav. Neurosci.

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Increasing attention has been given to understanding resilience to brain diseases, often described as brain or cognitive reserve. Among the protective factors for the development of resilience, physical activity/exercise has been considered to play an important role. Exercise is known to induce many positive effects on the brain. As such, exercise represents an important tool to influence neurodevelopment and shape the adult brain to react to life's challenges. Among many beneficial effects, exercise intervention has been associated with cognitive improvement and stress resilience in humans and animal models. Thus, a growing number of studies have demonstrated that exercise not only recovers or minimizes cognitive deficits by inducing better neuroplasticity and cognitive reserve but also counteracts brain pathology. This is evidenced before disease onset or after it has been established. In this review, we aimed to present encouraging data from current clinical and pre-clinical neuroscience research and discuss the possible biological mechanisms underlying the beneficial effects of physical exercise on resilience. We consider the implication of physical exercise for resilience from brain development to aging and for some neurological diseases. Overall, the literature indicates that brain/cognitive reserve built up by regular exercise in several stages of life, prepares the brain to be more resilient to cognitive impairment and consequently to brain pathology.

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“…However, the unbiased estimation of the number of cells of interest by the stereological method is accurate [ 82 ]. Using the unbiased stereological method, Hashiguchi et al reported that 4 weeks of ladder-climbing exercise did not affect the total number of microglia in the dorsal hippocampus of APP/PS1 mice at the age of 8 months [ 83 ]; however, they did not quantify the number of microglia in the subregions of the hippocampus. In our study, we showed that long-term voluntary running significantly increased the total number of microglia in the DG of 13-month-old APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Zhu

Peng

et al. 2022

J Neuroinflammation

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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.

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Resistance Exercise Decreases Amyloid Load and Modulates Inflammatory Responses in the APP/PS1 Mouse Model for Alzheimer’s Disease

Cited by 34 publications

References 65 publications

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

The Contribution of Physical Exercise to Brain Resilience

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

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