Platelet factors attenuate inflammation and rescue cognition in ageing

  • Nature. 2023 Aug;620(7976):1071-1079. doi: 10.1038/s41586-023-06436-3.
Adam B Schroer  #  1 ,  Patrick B Ventura  #  2 ,  Juliana Sucharov  2  3 ,  Rhea Misra  2  3 ,  M K Kirsten Chui  2 ,  Gregor Bieri  2 ,  Alana M Horowitz  2  3 ,  Lucas K Smith  2  3 ,  Katriel Encabo  4 ,  Imelda Tenggara  4 ,  Julien Couthouis  5 ,  Joshua D Gross  6 ,  June M Chan  4  7 ,  Anthony Luke  8 ,  Saul A Villeda  9  10  11  12
Affiliations
  • 1. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • 2. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
  • 3. Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
  • 4. Department of Urology, University of California San Francisco, San Francisco, CA, USA.
  • 5. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 6. Department of Cell Biology, Duke University, Durham, NC, USA.
  • 7. Departments of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
  • 8. Department of Orthopaedics, University of California San Francisco, San Francisco, CA, USA.
  • 9. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • 10. Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • 11. Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • 12. Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 37587343 DOI: 10.1038/s41586-023-06436-3
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.