Exercise plasma boosts memory and dampens brain inflammation via clusterin

Miguel, Zurine De; Khoury, Nathalie; Betley, Michael J.; Lehallier, Benoit; Willoughby, Drew; Olsson, Niclas; Yang, Andrew C.; Hahn, Oliver; Lu, Nannan; Vest, Ryan; Bonanno, Liana; Yerra, Lakshmi; Zhang, Lichao; Saw, Nay L.; Fairchild, J. Kaci; Lee, Davis; Zhang, Hui; McAlpine, Patrick L.; Contrepois, Kévin; Shamloo, Mehrdad; Elias, Joshua E.; Rando, Thomas A.; Wyss‐Coray, Tony

doi:10.1038/s41586-021-04183-x

Cited by 181 publications

(172 citation statements)

References 70 publications

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“…No reuse allowed without permission. inhibition of neuroinflammation 23,27,28,32 , consistent with our findings in the hippocampus of aging and MAPT P301S mice with enhanced skeletal muscle proteostasis. Although the mechanisms responsible for the transduction of these neurotrophic, anti-inflammatory signals into the hippocampus remain poorly understood, some evidence suggests that astrocytes at the bloodbrain barrier interface monitor cerebral perfusion and control systemic circulation to maintain brain blood flow 85 .…”

Section: Discussionsupporting

confidence: 91%

“…Geroprotective interventions that target the CNS can have direct effects on brain plasticity, with well-documented benefits on hippocampal-dependent cognitive functions 6,28,39,40 . Given the rejuvenation of proteostasis, reduction in neuroinflammation and increase in BDNF expression observed in the aging hippocampi of cTFEB;HSACre transgenic mice, we pursued neurocognitive testing in aged (16-18 months-old) control and cTFEB:HSACre mice (n=10-12/genotype, males and females, littermates).…”

Section: Improved Performance In Neurocognitive Testing In Aging Ctfe...mentioning

confidence: 99%

“…rescue function in the aging CNS 25,27 by decreasing neuroinflammation 28 and enhancing neurogenesis 23 . Studies have further demonstrated that increasing the circulating levels of these individual factors in peripheral circulation is sufficient to rejuvenate the aged CNS 25,29,30 , supporting the existence of 'pro-youth' circulating factors with CNS targeting effects.…”

Section: Introductionmentioning

confidence: 99%

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Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Matthews

Birnbaum

Gromova

et al. 2022

Preprint

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Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Here we report the generation of a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of TFEB. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity, reduce neuroinflammation and promotes transcriptional remodeling of the aging CNS, preserving cognition/memory in aging mice. Enhancing skeletal muscle proteostasis also reduced neuroinflammation and accumulation of tau-associated pathological hallmarks in a mouse model of tau pathology and was accompanied by increased secretion of CNS-targeting circulating factors from skeletal muscle. Our results implicate maintenance of skeletal muscle proteostasis throughout aging to direct regulations of the aging CNS metabolism and function, and suggest that skeletal-muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 91%

Section: Improved Performance In Neurocognitive Testing In Aging Ctfe...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Matthews

Birnbaum

Gromova

et al. 2022

Preprint

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“…Notably, environmental factors such as exercise and enriched home cages for rodents enhance NSPC proliferation [ 34 ] and the differentiation and survival [ 35 ] of new adult-born neurones, respectively. These phenomena have led to the identification of several factors generated outside of the CNS that regulate adult hippocampal neurogenesis (AHN), including irisin [ 36 ], klotho [ 37 ], cathepsin B [ 38 ], clusterin [ 39 ], eotaxin [ 40 ], growth differentiation factor11 (GDF11) [ 41 ], β 2 microglobulin (B2M) [ 42 ], and glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1) [ 43 ]. Similarly, calorie restriction increases AHN primarily by supporting differentiation and survival [ 44 ] via ghrelin signalling [ 12 , 45 ].…”

Section: Central Actions Of Ghrelinmentioning

confidence: 99%

Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis

Sassi

Morgan

Davies

2022

Cells

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Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson’s disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson’s disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin’s role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia.

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“…Parabiosis experiments have shown that an aged systemic environment negatively impacts neurogenesis, cognitive function and activates microglia of young mice 15,16 . Contrariwise, plasma derived from young and physical active mice is able to rejuvenate multiple tissues including the brain [17][18][19] and rescue neuroin ammation and neurodegeneration in a mouse model for AD and acute brain in ammation 17,20 .…”

Section: Introductionmentioning

confidence: 99%

Aging blood factors promote CD8+ T cell infiltration in the adult mouse brain

Olst

Kamermans

Hulshof

et al. 2022

Preprint

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Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we first characterized the immune landscape upon aging in 20-month-old mice using cytometry by time-of-flight (CyTOF) and observed that memory T cells expanded in the circulation and that specifically effector CD8+ T cells expressing programmed cell death protein 1 (PD-1) and tissue-resident memory CD8+ T cells accumulated in the aged brain. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Finally, we found an accumulation of CD8+ T cells within the brain parenchyma of plasma-treated mice, which coincided with expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature and increased numbers of proliferating microglia. Taken together, our data highlight a role for CD8+ T cells in the aged brain and suggests involvement of age-associated systemic factors that mediate CD8+ T cell migration and expansion in the brain parenchyma.

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Exercise plasma boosts memory and dampens brain inflammation via clusterin

Cited by 181 publications

References 70 publications

Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis

Aging blood factors promote CD8+ T cell infiltration in the adult mouse brain

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