Platelet factors attenuate inflammation and rescue cognition in ageing

Adam B. Schroer (), Patrick B. Ventura, Juliana Sucharov, Rhea Misra, M. K. Kirsten Chui, Gregor Bieri, Alana M. Horowitz, Lucas K. Smith, Katriel Encabo, Imelda Tenggara, Julien Couthouis, Joshua D. Gross, June M. Chan, Anthony Luke and Saul A. Villeda ()
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Adam B. Schroer: University of California San Francisco
Patrick B. Ventura: University of California San Francisco
Juliana Sucharov: University of California San Francisco
Rhea Misra: University of California San Francisco
M. K. Kirsten Chui: University of California San Francisco
Gregor Bieri: University of California San Francisco
Alana M. Horowitz: University of California San Francisco
Lucas K. Smith: University of California San Francisco
Katriel Encabo: University of California San Francisco
Imelda Tenggara: University of California San Francisco
Julien Couthouis: Stanford University School of Medicine
Joshua D. Gross: Duke University
June M. Chan: University of California San Francisco
Anthony Luke: University of California San Francisco
Saul A. Villeda: University of California San Francisco

Nature, 2023, vol. 620, issue 7976, 1071-1079

Abstract: Abstract Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Date: 2023
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DOI: 10.1038/s41586-023-06436-3

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