The premise of the three studies was different — Schroer et al. sought to determine whether and how platelets from young mice contribute to a well-described beneficial effect of the transfer of young-to-old mice blood on brain function; Park et al. focused on deciphering the cellular and molecular mechanism that underlie the beneficial effect of the longevity factor klotho on cognition; and Leiter et al. aimed to understand whether PF4, which they previously implicated in hippocampal neurogenesis, is released by exercise and could also affect other brain functions. Although the starting points were different, the three studies converged by showing that the treatment of older mice with mouse or human PF4 restored cognitive function in the aged brain, thus implicating platelets and their released factor PF4 in the regulation of cognition for the first time.
Schroer et al. showed that platelets from young mice and humans release more PF4 than platelets from aged mice and individuals, and that the rejuvenating effect of PF4 was indirect, mediated in part by the PF4 receptor CXCR3. Treatment with PF4 resulted in the reversion of the ratio of different immune cell types from one that is typical for old mice to one that is characteristic for young mice, resulting in decreased hippocampal inflammation and increased synaptic plasticity. Park et al. showed that klotho increased levels of several platelet factors in plasma, including PF4, but the well-described beneficial effects of klotho on cognition were still seen in mice lacking PF4, which suggests that this platelet factor is sufficient but not necessary to enhance synaptic plasticity and cognition. Unlike Schroer et al., Park et al. suggested that the effect of PF4 on the brain is direct and that the platelet molecule can cross the blood–brain barrier and affect brain cells through yet unknown mechanisms. Leiter et al. confirmed that both exercise and PF4 stimulate hippocampal neurogenesis and added further granularity to the process by showing that PF4 mediates the effect of exercise by affecting the survival or maturation of newborn neurons rather than their proliferation. The group further showed that neurogenesis is necessary for the rejuvenating effect of PF4 on cognition and is associated with transcriptional changes in adult neural precursor cells.
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