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Exercise plasma boosts memory and dampens brain inflammation via clusterin
Open accessAbstract
Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration 1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus 2-4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.
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“Together, these results demonstrate that RP effectively antagonizes the neuroinflammatory response to LPS in the hippocampus.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > RP reduces neuroinflammation
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“Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
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“Importantly, repeated control injections of saline through the retro-orbital vein under anaesthesia did not significantly alter hippocampal cell proliferation and survival”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“Similarly, RP improved their performance in the Morris water maze (Fig. 1e–g and Extended Data Fig. 2c)–a test of spatial learning and memory.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“Furthermore, RP induced a twofold expansion of surviving NSPCs compared with CP.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
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“Pathway analysis of the most significant 500 DEGs pointed to response to cytokine, regulation of the innate immune response, regulation of the response to stimulus and cytokine production”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > RP reduces neuroinflammation
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“However, RP did not significantly increase the number of surviving mature neurons”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
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“and, instead, lead to a twofold increase in the survival of newly produced astrocytes”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“without affecting their response to auditory cues, activity in a light–dark arena or anxiety levels in the activity chamber”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“We observed that 28 d of running was sufficient to increase overall cell survival (BrdU+ cells), including neurons(NeuN+BrdU+ cells), the number of neural stem and progenitor cells (NSPCs; Sox2+GFAP− cells) and astrocytes (GFAP+BrdU+ cells) and that this effect was most prominent in mice aged 3 months”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“the top 250 DEGs pointed to a downregulation of the acute inflammatory response as the most significantly affected biological pathway, followed by upregulation of cell junction organization and negative regulation of proteolysis”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“We identified 235 unique proteins across the two experimental conditions; of these, 23 were downregulated and 26 were upregulated in the plasma of running mice”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
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“In an independent experiment, RP from mice that had access to a running wheel for 28 d replicated these findings, whereas RP from mice that had access to a running wheel for 7 d or 14 d increased only the neuroblast counts and did not increase cell proliferation and survival”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“Consistent with the effects on neurogenesis, injection of RP, but not CP, increased the contextual learning and memory of mice in the fear conditioning paradigm”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
plaindirect- Asserted: passes — The authors put it forward as true.
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“We found that rCLU reversed many of the genes that are abnormally expressed in the BECs of APP transgenic mice”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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“We observed 1,952 significant differentially expressed genes (DEGs), of which 61% were downregulated and 39% were upregulated after RP treatment”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
plaindirect- Asserted: passes — The authors put it forward as true.
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“Biological pathway analysis pointed to activation of the alternative pathway of the complement system and endothelial cell differentiation”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
plaindirect- Asserted: passes — The authors put it forward as true.
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“Notably, recipient mice that received RP showed a significant increase in total proliferating cells, DCX+ neuroblasts and surviving cells compared with CP-recipient mice”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
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“administration of rCLU, but not saline, reversed the expression of multiple transcripts in the hippocampal BECs of mice that were systemically inoculated with LPS”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
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In the paper
“assessment of fibrinolysis and measurement of clot formation over time showed a significant reduction in the maximum clot formed in RP compared with in CP, yet no differences in clot lysis time or the time to half lysis and in vivo blood clotting after tail clipping were found in runner and control mice”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Strikingly, treatment with RP, but not CP, reversed the expression of a large number of these genes (r = −0.78) such that the hippocampal transcriptome of RP-treated mice had greater similarity to that of control mice that did not receive LPS”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > RP reduces neuroinflammation
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“RP reduced the expression of genes–validated using quantitative PCR (qPCR) (Extended Data Fig. 3b and Supplementary Table 5)–of the toll-like receptor (TLR) signalling pathway (Myd88, Tlr1 and Tlr2, and Irak3), the interferon pathway (Irf9, Infgr1, Stat1 and Stat3) as well as glial fibrillary acidic protein (Gfap), a sensitive indicator of astrocyte activation.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > RP reduces neuroinflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, the depletion of CLU largely abrogated the anti-inflammatory properties of RP, whereas depletion of FH, PEDF or LIFR had little or no effect”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Analysis of female RP and CP using TMT MS identified that 31 out of 567 detected proteins were significantly changed with running (Extended Data Fig. 5a, b), with 4 belonging to the complement and coagulation pathways–C4BPA, F12 and MASP1 were downregulated and C1INH was upregulated with exercise”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our proteomic analysis also showed increased levels of CLU, complement factor H (FH), complement 1 inhibitor (C1INH), and a concerted increase in the C8 alpha and gamma chains of the C8 component of the terminal pathway for the formation of the membrane attack complex”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“while complement factor 3 (C3), coagulation factor II (FII/prothrombin), uPA and plasminogen (PLG) were decreased”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The commercial aptamer-based proteomic platform accurately measures the targeted complement and coagulation proteins in human plasma.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the brain, CLU is expressed in astrocytes but does not change in response to RP”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“CLU was significantly increased and FX decreased in the patients who exercised”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The commercial aptamer-based proteomic platform accurately measures the targeted complement and coagulation proteins in human plasma.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Graphs show percentage of freezing behaviour in response to the light/tone cues associated with the fear stimulus in CP and RP recipient mice (n = 18–20 per group). Means ± s.e.m; Unpaired Student’s two-tailed t test, N.S. not significant.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plainn = 18- Asserted: passes — The authors put it forward as true.
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In the paper
“Measuring the activity of the classical, alternative, and lectin complement pathways in control versus runner’s plasma. Plots show absorbance at 450nm indicative of levels of membrane C5b-9 attack complex formation induced by IgM, LPS, or Mannose Binding Lectin (MBL) respectively (n = 10–13 per group). Means ± s.e.m; Unpaired Student’s two-tailed t test; n.s., not significant.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plainn = 10- Asserted: passes — The authors put it forward as true.
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In the paper
“Amount of blood lost in runner and control mice after tail clipping as measured by the haemoglobin concentration (n = 7 per group). Means ± s.e.m; unpaired Student’s two-tailed t test; n.s., not significant.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plainn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“CP and RP infused mice show comparable activity and velocity in the activity chamber (n = 13–14 per group) and percentage of time spent in the light arena (n = 12 per group). Means ± s.e.m; unpaired Student’s two-tailed t test; N.S., not significant.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plainn = 13- Asserted: passes — The authors put it forward as true.
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In the paper
“Representative GO enrichment categories of LPS significantly regulated genes. Lengths of bars represent negative ln-transformed P using two-sided Fisher’s exact test. Colours indicate gene-wise log2 fold-changes (log2(FC)) between (e) LPS and Saline treatment or (f) LPS+rCLU and LPS treatment. Numbers beside bars indicate DEGs induced by LPS in that GO category.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“Venn Diagram showing the number of unique and common genes that are increased by LPS and APP and reversed by CLU and reduced by LPS and APP and reversed by CLU (Extended Data Fig. 8f,g and 9e).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Venn diagrams depicting the overlap of DEGs (shown in panel a) in whole cortex of mice inoculated with LPS or LPS+rCLU, relative to the Saline-injected controls.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaincorrelationaln = 8- Asserted: passes — The authors put it forward as true.
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In the paper
“Number of DEGs (Wald test; P < 0.1) between Saline-treated mice (n = 4) and either LPS (n =8) or LPS+rCLU (n = 7) injected animals.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaincorrelationaln = 8 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Scatter plots show a list of selected genes altered in BECs (arterial, capillary, and venous) by chronic (APP) inflammation and reversed by CLU treatment. Coloured genes represent genes that pass the cutoff fold change of 1.1. Green: Genes increased by inflammation and reversed by CLU. Blue: Genes reduced by inflammation and reversed by CLU.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“Long-term voluntary exercise in mouse models of Alzheimer’s disease (AD) and related disorders improve learning and memory, and decrease neuroinflammation3,7,8.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
What the sources say
- Not checked yetcites [3] He, X. F. et al. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front. Mol. Neurosci. 10, 144 (2017). source
- Not checked yetcites [7] Horder, H. et al. Midlife cardiovascular fitness and dementia: a 44-year longitudinal population study in women. Neurology 90, e1298–e1305 (2018). source
- Not checked yetcites [8] da Costa Daniele, T. M. et al. Exercise effects on brain and behavior in healthy mice, Alzheimer’s disease and Parkinson’s disease model—a systematic review and meta-analysis. Behav. Brain Res. 383, 112488 (2020). source
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In the paper
“Factors including IGF-1 (ref. 9), VEGF10 and PF4 (ref.11) increase hippocampal neurogenesis in young mice”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
What the sources say
- Not checked yetcites [9] Trejo, J. L., Carro, E. & Torres-Aleman, I. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634 (2001). source
- Not checked yetcites [10] Fabel, K. et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur. J. Neurosci. 18, 2803–2812 (2003). source
- Not checked yetcites [11] Leiter, O. et al. Exercise-induced activated platelets increase adult hippocampal precursor proliferation and promote neuronal differentiation. Stem Cell Rep. 12, 667–679 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2–4”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
What the sources say
- Not checked yetcites [2] Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615 (2011). source
- Not checked yetcites [3] He, X. F. et al. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front. Mol. Neurosci. 10, 144 (2017). source
- Not checked yetcites [4] van Praag, H., Christie, B. R., Sejnowski, T. J. & Gage, F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl Acad. Sci. USA 96, 13427–13431 (1999). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
What the sources say
- Not checked yetcites [1] Prakash, R. S., Voss, M. W., Erickson, K. I. & Kramer, A. F. Physical activity and cognitive vitality. Annu. Rev. Psychol. 66, 769–797 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“GPDL1 rescues the age-related loss in neurogenesis and cognition in old mice12”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
What the sources say
- Not checked yetcites [12] Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings indicate that plasma factors from running male mice are largely sufficient to reproduce the effects of running on hippocampal neurogenesis, improve learning and memory, and downregulate the baseline expression of inflammatory genes in the young adult hippocampus.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Runner plasma improves cognition
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The complement and coagulation protein changes seen after exercise in humans reflect the same biology as the changes observed in mice.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show that changes in plasma as a result of physical aerobic exercise are sufficient to recapitulate the beneficial effects of exercise on neurogenesis and memory, and to reduce hippocampal inflammation in non-exercised mice and mice with experimentally induced neuroinflammation.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The complement and coagulation protein changes seen after exercise in humans reflect the same biology as the changes observed in mice.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“supporting the hippocampal anti-inflammatory effect of this protein.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Anti-inflammatory effects of exercise have previously been linked to changes in the secretion of immune-modulatory cytokines from muscle and fat tissue, the mobilization of regulatory T cells from lymphoid organs, and the reduction of inflammatory monocytes in the blood2.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [2] Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615 (2011). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Differences in physical exertion between sexes17 and direct effects of the oestrous cycle on the complement and coagulation pathways18 may explain some of the differential effects based on sex.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Running alters complement pathway proteins
What the sources say
- Not checked yetcites [17] Hicks, A. L., Kent-Braun, J. & Ditor, D. S. Sex differences in human skeletal muscle fatigue. Exerc. Sport Sci. Rev. 29, 109–112 (2001). source
- Not checked yetcites [18] Yip, K. S., Suvorov, A., Connerney, J., Lodato, N. J. & Waxman, D. J. Changes in mouse uterine transcriptome in estrus and proestrus. Biol. Reprod. 89, 13 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effects are linked to complement and coagulation pathways including CLU, which can target BECs and broadly reduce interferon signalling.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The complement and coagulation protein changes seen after exercise in humans reflect the same biology as the changes observed in mice.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CLU may similarly reduce brain inflammation by targeting the vasculature, although other mechanisms are probably also involved.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Notably, GPDL1–which is an exercise-induced plasma protein that has been reported to improve cognition in old mice12–is also produced in the liver.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [12] Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In neurodegeneration, the complement pathway is activated, and inhibiting the complement proteins C1q or C3 results in less neuroinflammation, Aβ plaques and synapse loss29,30.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [29] Yin, C. et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat. Med. 25, 496–506 (2019). source
- Not checked yetcites [30] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The experimenters were blinded to the treatment.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Behaviour
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were randomly assigned to the experimental conditions.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Animals
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Images of immunofluorescent sections were obtained, quantified and analysed by an observer who was blinded to the treatment.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Imaging and cell quantification
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Next, running mice were randomly housed in the activity cages in pairs with free access to unlocked wheels and control mice were housed in pairs in standard animal facility cages.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Voluntary exercise
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Complement and coagulation proteins, including CLU, are largely produced by hepatocytes28”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [28] Zhou, Z., Xu, M. J. & Gao, B. Hepatocytes: a key cell type for innate immunity. Cell. Mol. Immunol. 13, 301–315 (2016). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“plasma CLU levels are increased in patients with AD and MCI32, possibly as a compensatory mechanism.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [32] Hsu, J. L. et al. Plasma biomarkers are associated with agitation and regional brain atrophy in Alzheimer’s disease. Sci. Rep. 7, 5035 (2017). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“polymorphisms in CLU are linked to AD19,20”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [19] Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009). source
- Not checked yetcites [20] Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Importantly, RP improves cognitive function and recapitulates the effects of exercise on neural stem cell activity possibly by reducing the baseline negative effects of inflammation on adult neurogenesis and cognition34,35.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
What the sources say
- Not checked yetcites [34] Lee, J. W. et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J. Neuroinflammation 5, 37 (2008). source
- Not checked yetcites [35] Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“systemically administered CLU binds to BECs and reduces their inflammatory gene expression in experimentally inflamed mouse brains, in part by reducing interferon signalling”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Dead cells were excluded by staining with SYTOX Blue Dead Cell Stain (1:2,000, Thermo Fisher Scientific, S34857).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Isolation of primary BECs
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For the APP samples, all of the cell suspension was loaded after getting lower than anticipated yields from sorting. For the other samples, 4,000 cells were targeted.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Single-cell RNA-seq and library preparation
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“FSC-A and FSC-W blotting was used to discriminate single cells from cell doublets/aggregates.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Isolation of primary BECs
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“To determine the samples size for the single-cell sequencing studies, we used previous studies13,26 and performed preliminary studies to confirm that we will obtain enough BECs for statistical analysis (not included in the manuscript).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Isolation of primary BECs
What the sources say
- Not checked yetcites [13] Chen, M. B. et al. Brain endothelial cells are exquisite sensors of age-related circulatory cues. Cell Rep. 30, 4418–4432 (2020). source
- Not checked yetcites [26] Yang, A. C. et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 583, 425–430 (2020). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Portions of each sample were used to check ion distributions and labelling efficiency.”
- Also stated in: § MS analysis · plain
“Portions of each sample were used to check ion distributions and labelling efficiency.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > MS analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § MS analysis · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Filtering criteria were applied to remove low-quality cells and doublets. Cells that had at least 600 features, a maximum of 6,000 features and 10% mitochondrial RNA were included in the downstream analysis.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Single-cell RNA-seq and data analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA was isolated from hippocampal tissue as previously described and the quality was validated using the Agilent 2100 Bioanalyzer (Stanford PAN Facility).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > RNA-seq analysis of the hippocampus
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The samples were processed under Good Laboratory Practice54 for intrarun normalization and calibration and passed all quality-control requirements.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > MS analysis
What the sources say
- Not checked yetcites [54] SOMAscan Technical White Paper (Somalogic, 2015); http://www.somalogic.com/wp-content/uploads/2016/08/SSM-002-Rev-3-SOMAscan-Technical-White-Paper.pdf
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“were purchased from Jackson Labs and housed in randomized groups of 2–4 mice, before any exercise or plasma injections.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Animals
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Diagnosis was based on the National Institute on Aging/Alzheimer’s Association criteria52.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > MS analysis
What the sources say
- Not checked yetcites [52] Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 270–279 (2011). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CD11b+ and CD45+ cells were gated to exclude monocytes/macrophages and microglia.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Isolation of primary BECs
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples were sent to Novogene for sequencing, where they were first assessed for library quality on a single lane of the HiSeq System followed by deep sequencing on a NovaSeq S4 flow cell to ensure >20,000 reads per cell as recommended.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Single-cell RNA-seq and library preparation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All of the experiments were performed in accordance with institutional guidelines approved by the VA Palo Alto Committee on Animal Research.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Sample size was determined using previous literature4,10,12 to estimate an optimal n for our studies on the RP effects on neuroplasticity and behaviour.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Behaviour
What the sources say
- Not checked yetcites [4] van Praag, H., Christie, B. R., Sejnowski, T. J. & Gage, F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl Acad. Sci. USA 96, 13427–13431 (1999). source
- Not checked yetcites [10] Fabel, K. et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur. J. Neurosci. 18, 2803–2812 (2003). source
- Not checked yetcites [12] Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“P values were adjusted for multiple testing and significant DEGs were defined by a cut-off of adjusted P < 0.1, as suggested for analyses using Deseq2 (ref. 39).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > RNA-seq analysis of the whole cortex
What the sources say
- Not checked yetcites [39] Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Validation of changes in gene expression in response to runner plasma infusions and validation of changes in proteins with running.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plaincorrelationaln = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Validation of proteins captured with shotgun-LC MS1 using TMT-LC MS3 detection and analysis.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
plainn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The rise in plasma CLU among patients after the exercise program is caused by the exercise itself rather than by other changes over time.
“Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU.”
The paper relies on this without support.
Before this study, changes in complement and coagulation cascades had not been implicated in exercise effects on brain neuroinflammation.
“To our knowledge, changes in the complement and coagulation cascadeshave not been implicated in the effects of exercise and in reducing neuroinflammation within the brain.”
The paper relies on this without support.
The commercial aptamer-based proteomic platform accurately measures the targeted complement and coagulation proteins in human plasma.
“we measured 8 out of the top 13 complement/coagulation proteins, including CLU identified in mice, using a commercial aptamer-based proteomic platform in 20 veterans with amnestic mild cognitive impairment before and 6 months after a physical exercise intervention.”
The paper relies on this without support.
The complement and coagulation protein changes seen after exercise in humans reflect the same biology as the changes observed in mice.
“Consistent with the findings in mice, CLU was significantly increased and FX decreased in the patients who exercised”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Clusterin, one of the complement cascade inhibitors, can bind to the receptor on brain endothelial cells and reduce the expression of inflammatory genes in an AD mouse model.129”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [129]
In the citing paper
“According to recent reports, replenishing clusterin and platelet factor 4 (PF4) ameliorates neuroinflammation,384,385 and oleoylethanolamide (OEA) enhances microglial phagocytosis,386 all of shese contribute to cognitive improvement and neuroprotection.”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [384]
In the citing paper
“Hence, the benefit of GPLD1 (REF.148) and other exerkines on brain structure and function might relate to its peripheral effects, such as the complement signalling cascade149,158, or coagulation159.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [149]
In the citing paper
“Evidence is now accumulating that factors released from non-neuronal tissue148–152 and delivered via the vasculature to the brain might have important roles in synaptic plasticity, memory function and mood regulation150.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [149]
In the citing paper
“Since 2020, several studies have transferred plasma from exercised animals into sedentary animals, with subsequent improvements in cognitive function, supporting the presence of a transferable factor in improving cognitive function148,149.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [149]
In the citing paper
“This paper demonstrated that plasma transfer from exercised young mice to sedentary young mice reduces brain inflammation and improves cognitive function”
From Exerkines in health, resilience and disease (2022) · cites this paper as [149]
In the citing paper
“supporting the potential of transferable anti-inflammatory exerkines in improving brain function.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [149]
In the citing paper
“blood factors that can influence NSC ageing and rejuvenation include inflammatory cytokines (for example, CXCL11) (likely circulating in the blood), circulating enzymes produced by the liver and complement factors (likely circulating in the blood146–148)”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [146]
In the citing paper
“Transfer of plasma from exercised mice to non-exercised aged mice enhanced neurogenesis and cognitive function146,147.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [146]
In the citing paper
“First, exercise can increase the levels of inhibitors of the complement cascade, including clusterin146.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [146]
In the citing paper
“Depletion of clusterin abrogates the beneficial effects of plasma from exercised mice on aged cognitive function.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [146]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > BrdU, EdU, LPS and rCLU preparation and administration
“To assay proliferation, EdU was administered 12 h before euthanasia.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
“EdU was administered 24 h before sacrifice.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Discussion
“Notably, GPDL1–which is an exercise-induced plasma protein that has been reported to improve cognition in old mice12–is also produced in the liver.”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Extended Data
“Glycosylphosphatidylinositol specific phospholipase D1 (GPLD1) | ↑ Increase in plasma after 6 weeks of free running wheel”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > Methods > Single-cell RNA-seq and data analysis
“To identify genes and pathways modified by LPS treatment or by AD and reversed by CLU treatment we used a fold change cut-off of 1.1 (Fig. 4d, e).”
§ Exercise plasma boosts memory and dampens brain inflammation via clusterin > CLU reduces hippocampal inflammation
“CLU was significantly increased and FX decreased in the patients who exercised (Fig. 4d and Supplementary Tables 17–20)”
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Metadata
- Authors
- De Miguel, Z., Khoury, N., Betley, M. J., Lehallier, B., Willoughby, D., Olsson, N., Yang, A. C., Hahn, O., Lu, N., Vest, R. T., Bonanno, L. N., Yerra, L., Zhang, L., Saw, N. L., Fairchild, J. K., Lee, D., Zhang, H., McAlpine, P. L., Contrepois, K., Shamloo, M., Elias, J. E., Rando, T. A., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Stanford University (US)
- ORCID
- Venue
- Nature
- Published
- 2021-12-08
- Volume
- 600
- Issue
- 7889
- Pages
- 494-499
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9721468
- OpenAlex
- W4200434404
- Cited by
- 422
- References
- 70
- Citations by year
- 2026: 67 · 2025: 116 · 2024: 100 · 2023: 83 · 2022: 54 · 2021: 2
- FWCI
- 23.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001319)
- National Institute on Aging (F32AG067652, R01AG047820, P01AG036695, P30AG066515, R01AG071783)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Oncology › Clusterin in disease pathology
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- physical activity, plasma, clusterin, neuroinflammation, Alzheimer's disease, cognitive aging, hippocampus, plasma proteomics, brain endothelial cells, voluntary running, sedentary mice, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Encephalitis, Humans, Proteomics, Endothelial Cells, Clusterin, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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