Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice

Cana Park; Oliver Hahn; Shweta Gupta; Arturo J Moreno; Francesca Marino; Blen Kedir; Dan Wang; Saul A Villeda; Tony Wyss-Coray; Dena B Dubal

doi:10.1038/s43587-023-00468-0

Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice

Nat Aging. 2023 Sep;3(9):1067-1078. doi: 10.1038/s43587-023-00468-0. Epub 2023 Aug 16.

Authors

Cana Park¹, Oliver Hahn², Shweta Gupta¹, Arturo J Moreno¹, Francesca Marino^{1

3}, Blen Kedir², Dan Wang¹, Saul A Villeda^{4

5

6

7}, Tony Wyss-Coray^{2

8

9

10}, Dena B Dubal^{11

12

13

14}

Affiliations

¹ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
³ Neurosciences Graduate Program, University of California, San Francisco, CA, USA.
⁴ Department of Anatomy, University of California, San Francisco, CA, USA.
⁵ Department of Physical Therapy and Rehabilitation Science, San Francisco, CA, USA.
⁶ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA.
⁷ Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
⁸ The Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
⁹ Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
¹¹ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. Dena.dubal@ucsf.edu.
¹² Neurosciences Graduate Program, University of California, San Francisco, CA, USA. Dena.dubal@ucsf.edu.
¹³ Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA. Dena.dubal@ucsf.edu.
¹⁴ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. Dena.dubal@ucsf.edu.

Abstract

Platelet factors regulate wound healing and can signal from the blood to the brain^1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein^3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Animals
Blood Coagulation Factors
Cognition
Longevity*
Mice
Platelet Factor 4

Substances

Blood Coagulation Factors
Platelet Factor 4
Kl protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding