Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice

Nature Communications · 13 authors, 6 centres

AI SUMMARY

FIDELITY 95%

POPULATIONAged (18-20 month old) C57BL/6J mice and DCX^DTR^ transgenic mice

INTERVENTIONSystemic intravenous administration of recombinant mouse PF4 (500 ng every third day for 24 days)

COMPARISONSaline (0.9% sodium chloride) intravenous injections on the same schedule

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TL;DR

This study identifies platelets as necessary mediators of exercise-induced brain rejuvenation in aged mice, showing that the platelet-derived exerkine PF4 (CXCL4) is both sufficient and necessary for enhancing hippocampal neurogenesis and restoring cognitive function. Systemic administration of PF4 to aged mice increased neural precursor cell proliferation, dendritic growth of newborn neurons, and improved performance in multiple hippocampus-dependent memory tasks. These findings highlight PF4 as a potential therapeutic target for counteracting age-related cognitive decline.

Full summary

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**Background:** Physical exercise is known to counteract cognitive decline in aging and neurodegenerative diseases, but the molecular mediators of this effect are not fully understood. Exerkines, factors released into circulation during exercise, are thought to mediate brain benefits. Platelets, primarily known for hemostasis, are activated by exercise and release factors including the chemokine platelet factor 4 (PF4/CXCL4). This study investigates whether platelets and PF4 are necessary for exercise-induced hippocampal neurogenesis and cognitive rejuvenation in aged mice, and whether systemic PF4 can recapitulate these effects.

**Methods:** The study used young (8-week-old) and aged (18-20-month-old) C57BL/6J mice, PF4 knockout mice, and DCX^DTR^ transgenic mice (allowing selective ablation of newborn neurons). Exercise paradigms involved voluntary running wheel access for 4-28 days. Platelet activation was measured by flow cytometry (CD62P surface expression). Platelet depletion was achieved using antiplatelet serum. Systemic PF4 was administered via tail vein injections (500 ng every 2-3 days for 1-4 weeks). Hippocampal neurogenesis was assessed by immunohistochemistry for Ki67 (proliferation), DCX (immature neurons), BrdU/NeuN (newborn mature neurons), and dendritic tracing of DCX+ cells. Cognitive function was evaluated using novel object location, contextual fear conditioning, and active place avoidance tasks. Proteomic analysis of platelet lysates and RNA sequencing of EGF-sorted neural precursor cells were performed.

**Key Results:** - In young mice, systemic PF4 increased DCX+ immature neurons (p<0.01) but did not affect Ki67+ proliferation or recruit quiescent stem cells (CldU/IdU labeling). In vitro, PF4 promoted neuronal differentiation (increased β-III-tubulin+ cells) without affecting proliferation. - PF4 knockout mice had significantly lower baseline hippocampal neurogenesis (Ki67+ and DCX+ cells, p<0.05) and failed to show exercise-induced increases in neural precursor proliferation (WT RUN vs KO RUN, p<0.01). - In aged mice, 28 days of exercise significantly increased Ki67+ cells (p<0.05), DCX+ cells (p<0.01), and BrdU+NeuN+ newborn neurons (p<0.05). Platelet activation (CD62P+) peaked at 28 days (p<0.01). Platelet depletion abolished the exercise-induced increase in proliferation (p<0.01). - Systemic PF4 in aged mice increased Ki67+ cells (p<0.05), DCX+ cells (p<0.01), and dendritic length of DCX+ cells (total length, primary dendrite length, longest dendrite; p<0.05). PF4-treated mice showed improved cognition: increased time at novel location (p<0.05), higher freezing in contextual fear conditioning (p<0.01), and fewer entries into shock zone in active place avoidance (p<0.01). - In DCX^DTR^ mice, ablation of DCX+ cells with diphtheria toxin completely prevented PF4-induced cognitive improvements in the active place avoidance task (PF4 vs PF4+DT, p<0.05). - Proteomic analysis of platelets from young and aged runners identified 5 proteins upregulated at both ages (progranulin, properdin, tropomyosin, destrin, ubiquitin-associated and SH3 domain-containing protein B). RNA sequencing of EGF+ neural precursors revealed PF4-induced upregulation of genes involved in neuronal differentiation and learning/memory pathways.

**Clinical Implications:** This study identifies platelets as a novel source of exercise-induced exerkines that rejuvenate the aging brain, with PF4 emerging as a key mediator. Systemic PF4 administration recapitulates the cognitive benefits of exercise in aged mice in a neurogenesis-dependent manner. These findings suggest that PF4 or its downstream pathways could be developed as therapeutic agents for age-related cognitive decline, potentially offering an alternative for individuals unable to exercise. The study also highlights platelets as a reservoir of neurotrophic factors, supporting their use in regenerative medicine. However, translation to humans requires caution, as chronic platelet activation is linked to cardiovascular and neurodegenerative conditions, and the effects of long-term PF4 elevation are unknown.

PICO

PPOPULATION

Aged (18-20 month old) C57BL/6J mice and DCX^DTR^ transgenic mice

IINTERVENTION

Systemic intravenous administration of recombinant mouse PF4 (500 ng every third day for 24 days)

OOUTCOME

Increased hippocampal neurogenesis (Ki67+ proliferating cells, DCX+ immature neurons, dendritic length of DCX+ cells); improved cognitive function in novel object location, contextual fear conditioning, and active place avoidance tasks; neurogenesis dependence shown by ablation of DCX+ cells with diphtheria toxin in DCX^DTR^ mice

STUDY TYPE

RCT

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

95% · A

ORIGINAL PAPER

PMC10432533

Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice

Nature Communications

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ABSTRACT

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.

CITATION EXPORT

Odette Leiter, David Brici, Stephen J. Fletcher et al.. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-39873-9

AUTHORS

13 · 6 CENTRES

Odette Leiter, David Brici, Stephen J. Fletcher, Xuan Ling Hilary Yong, Jocelyn Widagdo, Nicholas Matigian, Adam B. Schroer, Gregor Bieri, Daniel G. Blackmore, Perry F. Bartlett, Victor Anggono, Saul A. Villeda, Tara L. Walker

1https://ror.org/00rqy9422grid.1003.20000 0000 9320 7537Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia
2https://ror.org/00rqy9422grid.1003.20000 0000 9320 7537Centre for Horticultural Science, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD 4072 Australia
3grid.1003.20000 0000 9320 7537Queensland Cyber Infrastructure Foundation Ltd, The University of Queensland, Brisbane, QLD 4072 Australia
4https://ror.org/043mz5j54grid.266102.10000 0001 2297 6811Department of Anatomy, University of California San Francisco, San Francisco, CA 94143 USA
5https://ror.org/043mz5j54grid.266102.10000 0001 2297 6811The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143 USA
6grid.266102.10000 0001 2297 6811Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA 94143 USA