Treadmill exercise inhibits amyloid-β generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation

Zhang, Xianliang; Zhao, Na; Xu, Bo; Chen, Xianghe; Li, Tuojian

doi:10.1097/wnr.0000000000001230

Cited by 24 publications

(12 citation statements)

References 34 publications

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“…The latter was proposed to be mediated through changes in APP processing [18] and an increase in clearance of Aβ [19], possibly resulting from an elevation of Aβ clearance proteins [20] and increased glymphatic clearance [21]. In addition, expression of other genes linked to AD progression such as β-site APP-cleaving enzyme 1 (BACE1), presenilin 1 (PS1), insulin-degrading enzyme (IDE), tau, and the receptor for advanced glycation end products (RAGE) are reduced as a consequence of exercise [22,23]. This may be due to a decrease in lipid-raft formation [23], activation of SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1) [12,24], and an increase in autophagy [19,25].…”

Section: Effects Of Exercise In Alzheimer's Diseasementioning

confidence: 99%

“…In addition, expression of other genes linked to AD progression such as β-site APP-cleaving enzyme 1 (BACE1), presenilin 1 (PS1), insulin-degrading enzyme (IDE), tau, and the receptor for advanced glycation end products (RAGE) are reduced as a consequence of exercise [ 22 , 23 ]. This may be due to a decrease in lipid-raft formation [ 23 ], activation of SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1) [ 12 , 24 ], and an increase in autophagy [ 19 , 25 ]. In addition, exercise has been proposed to mitigate mitochondrial dysfunction [ 11 , 26 ], delay disease-related white matter volume loss [ 27 – 30 ], reduce neuroinflammation [ 19 , 21 , 22 , 31 – 34 ] and oxidative stress [ 10 , 19 , 35 ], repress neuronal cell death [ 36 ], and favor adult neurogenesis [ 17 , 37 – 40 ].…”

Section: Introductionmentioning

confidence: 99%

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A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

et al. 2020

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Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.

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Section: Effects Of Exercise In Alzheimer's Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

et al. 2020

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“…• Treadmill exercise inhibited amyloidogenic APP cleavage and Aβ production in APP and presenilin-1 transgenic mice by inhibiting flotillin-1 levels and lipid raft formation [51] 13…”

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confidence: 99%

“…However, no significant differences in APP clustering or endocytosis were observed in mouse embryonic fibroblasts with no flotillin-1 expression [50]. Another study has indicated that treadmill exercise could inhibit amyloidogenic APP cleavage and subsequent Aβ production in the brain of APP and presenilin-1 transgenic mouse models, by suppressing lipid raft formation and flotillin-1 levels [51]. Furthermore, it has been reported that treatment of senescence-accelerated mouse prone 8 mice with Yizhijiannao granule, a Chinese medicinal compound, could downregulate flotillin-1 levels in the temporal lobes of the animals [52].…”

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confidence: 99%

Flotillin: A Promising Biomarker for Alzheimer’s Disease

Angelopoulou

Paudel

Shaikh

et al. 2020

JPM

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Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid rafts, as well as the endocytic pathways in amyloidogenic amyloid precursor protein (APP) processing and AD pathogenesis. The combination of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging. However, their invasive nature, the cost, and their availability often limit their use. In this context, an easily detectable marker for AD diagnosis even at preclinical stages is highly needed. Flotillins, being hydrophobic proteins located in lipid rafts of intra- and extracellular vesicles, are mainly involved in signal transduction and membrane–protein interactions. Accumulating evidence highlights the emerging implication of flotillins in AD pathogenesis, by affecting APP endocytosis and processing, Ca2+ homeostasis, mitochondrial dysfunction, neuronal apoptosis, Aβ-induced neurotoxicity, and prion-like spreading of Aβ. Importantly, there is also clinical evidence supporting their potential use as biomarker candidates for AD, due to reduced serum and CSF levels that correlate with amyloid burden in AD patients compared with controls. This review focuses on the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, further addressing their potential usage as disease biomarkers.

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“…Surprisingly, our data showed that males from the exercise group had increased plasma cholesterol, indicating a possible influence of sex hormones since estrogens are already known to be regulators of lipid metabolism. 47 Although the relationship between exercise and cholesterol levels is well established, [48][49][50] we speculate that the association between the withdrawal of exercise before pregnancy and stress may have led to this negative metabolic outcome. Groups were compared by a two-way ANOVA followed by the LSD post-hoc test.…”

Section: Discussionmentioning

confidence: 87%

Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice

Luft

Levices

Pedrazza

et al. 2020

J Dev Orig Health Dis

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Stressful events during the prenatal period have been related to hyperactive hypothalamic–pituitary–adrenal (HPA) axis responses as well as metabolic changes in adult life. Moreover, regular exercise may contribute to the improvement of the symptoms associated with stress and stress-related chronic diseases. Therefore, this study aims to investigate the effects of exercise, before the gestation period, on the metabolic changes induced by prenatal stress in adult mice. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS) and exercise before the gestational period plus PNS (EX + PNS). When adults, the plasmatic biochemical analysis, oxidative stress, gene expression of metabolic-related receptors and sex differences were assessed in the offspring. Prenatal stress decreased neonatal and adult body weight when compared to the pregestational exercise group. Moreover, prenatal stress was associated with reduced body weight in adult males. PNS and EX + PNS females showed decreased hepatic catalase. Pregestational exercise prevented the stress-induced cholesterol increase in females but did not prevent the liver mRNA expression reduction on the peroxisome proliferator-activated receptors (PPARs) α and γ in PNS females. Conversely, PNS and EX + PNS males showed an increased PPARα mRNA expression. In conclusion, pregestational exercise prevented some effects of prenatal stress on metabolic markers in a sex-specific manner.

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Treadmill exercise inhibits amyloid-β generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation

Cited by 24 publications

References 34 publications

A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

Flotillin: A Promising Biomarker for Alzheimer’s Disease

Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice

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