Physical Activity Rewires the Human Brain against Neurodegeneration

Santiago, José A.; Quinn, James P.; Potashkin, Judith A.

doi:10.3390/ijms23116223

Cited by 23 publications

(21 citation statements)

References 84 publications

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“…In this regard, the management of dysbiosis represents an additional tool to be further investigated for preventative or treatment purposes. In addition, studies focused on the role of physical activity in neurodegeneration provide evidence for a strong correlation between exercise and NDD; in particular, physical activity acts by directing transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases [ 98 ]. Physical activity combined with current available therapies, promises to be important for NDDs management and treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, physical activity-related switch genes involved in cognition and neurodegeneration have been identified [ 98 ]. These genes act via the upregulation of synaptic signaling pathways, conferring neuroprotection in AD and PD, and via the downregulation of genes involved in inflammation in AD, hence playing an important role in disease pathogenesis [ 98 ].…”

Section: Physical Activity and Nddsmentioning

confidence: 99%

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Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

Barati

Fabrizio

Strafella

et al. 2022

Genes

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In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of genetic and epigenetic factors, nutrients, and lifestyle will be presented, with particular emphasis on Alzheimer’s disease (AD) and Parkinson’s disease (PD). Metabolism, dietary habits, physical exercise and microbiota are part of a complex network that is crucial for brain function and preservation. This complex equilibrium can be disrupted by genetic, epigenetic, and environmental factors causing perturbations in central nervous system homeostasis, contributing thereby to neuroinflammation and neurodegeneration. Diet and physical activity can directly act on epigenetic modifications, which, in turn, alter the expression of specific genes involved in NDDs onset and progression. On this subject, the introduction of nutrigenomics shed light on the main molecular players involved in the modulation of health and disease status. In particular, the review presents data concerning the impact of ADH1B, CYP1A2, and MTHFR on the susceptibility and progression of NDDs (especially AD and PD) and how they may be exploited for developing precision medicine strategies for the disease treatment and management.

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Section: Discussionmentioning

confidence: 99%

Section: Physical Activity and Nddsmentioning

confidence: 99%

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

Barati

Fabrizio

Strafella

et al. 2022

Genes

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“…The transcription factor Nrf1 (NFE2L1), which is involved in the expression of proteasomal genes, was also identified as following this pattern. Genes involved in transcriptional repression and negative growth regulation were increased in PD subjects and decreased with exercise [ 149 ].…”

Section: Interventional Strategies To Correct Dysfunctional Mqc and D...mentioning

confidence: 99%

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Curtis

Seeds²,

Mattson

et al. 2022

Cells

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Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

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“…Switch genes are associated with drastic transcriptional changes and may play a critical role in disease pathogenesis. This bioinformatic method has successfully identified switch genes in numerous biological settings, including cancer ( Fiscon et al, 2018b ,c; Falcone et al, 2019 ), chronic obstructive pulmonary disease ( Paci et al, 2020 ), physical activity ( Santiago et al, 2022 ), AD ( Potashkin et al, 2019 ; Bottero et al, 2021 ), frontotemporal and vascular dementias ( Potashkin et al, 2020 ), and amyotrophic lateral sclerosis ( Santiago et al, 2021 ; Bottero et al, 2022 ). Further, sex-specific switch genes were identified in the blood of ALS patients ( Santiago et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

Santiago¹,

Quinn²,

Potashkin

2022

Front. Aging Neurosci.

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Sex-specific differences may contribute to Alzheimer’s disease (AD) development. AD is more prevalent in women worldwide, and female sex has been suggested as a disease risk factor. Nevertheless, the molecular mechanisms underlying sex-biased differences in AD remain poorly characterized. To this end, we analyzed the transcriptional changes in the entorhinal cortex of symptomatic and asymptomatic AD patients stratified by sex. Co-expression network analysis implemented by SWItchMiner software identified sex-specific signatures of switch genes responsible for drastic transcriptional changes in the brain of AD and asymptomatic AD individuals. Pathway analysis of the switch genes revealed that morphine addiction, retrograde endocannabinoid signaling, and autophagy are associated with both females with AD (F-AD) and males with (M-AD). In contrast, nicotine addiction, cell adhesion molecules, oxytocin signaling, adipocytokine signaling, prolactin signaling, and alcoholism are uniquely associated with M-AD. Similarly, some of the unique pathways associated with F-AD switch genes are viral myocarditis, Hippo signaling pathway, endometrial cancer, insulin signaling, and PI3K-AKT signaling. Together these results reveal that there are many sex-specific pathways that may lead to AD. Approximately 20–30% of the elderly have an accumulation of amyloid beta in the brain, but show no cognitive deficit. Asymptomatic females (F-asymAD) and males (M-asymAD) both shared dysregulation of endocytosis. In contrast, pathways uniquely associated with F-asymAD switch genes are insulin secretion, progesterone-mediated oocyte maturation, axon guidance, renal cell carcinoma, and ErbB signaling pathway. Similarly, pathways uniquely associated with M-asymAD switch genes are fluid shear stress and atherosclerosis, FcγR mediated phagocytosis, and proteoglycans in cancer. These results reveal for the first time unique pathways associated with either disease progression or cognitive resilience in asymptomatic individuals. Additionally, we identified numerous sex-specific transcription factors and potential neurotoxic chemicals that may be involved in the pathogenesis of AD. Together these results reveal likely molecular drivers of sex differences in the brain of AD patients. Future molecular studies dissecting the functional role of these switch genes in driving sex differences in AD are warranted.

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Physical Activity Rewires the Human Brain against Neurodegeneration

Cited by 23 publications

References 84 publications

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

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