Platelet factors attenuate inflammation and rescue cognition in ageing, 2023, Schroer et al.

SNT Gatchaman

SNT Gatchaman

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Platelet factors attenuate inflammation and rescue cognition in ageing
Schroer, Adam B.; Ventura, Patrick B.; Sucharov, Juliana; Misra, Rhea; Chui, M. K. Kirsten; Bieri, Gregor; Horowitz, Alana M.; Smith, Lucas K.; Encabo, Katriel; Tenggara, Imelda; Couthouis, Julien; Gross, Joshua D.; Chan, June M.; Luke, Anthony; Villeda, Saul A.

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.

Link | PDF (Nature)
 
The multi-million dollar question. They showed some corresponding aspects in humans.

Moreover, we detected elevated levels of PF4 in platelet-rich plasma derived from the blood of young compared with older healthy human individuals by western blot analysis
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They also treated the mice with human PF4.

To begin to investigate the translational potential of PF4, aged male mice were systemically administered with human PF4 (hPF4) derived from human platelets (5 μg ml−1), and hippocampal-dependent learning and memory was assessed using NOR and RAWM testing. No adverse effects or differences in overall activity were observed between the hPF4 and saline treatment groups. Aged mice treated with hPF4 were biased towards a novel object relative to a familiar object, whereas saline-treated mice showed no preference. All of the mice showed similar spatial learning ability during RAWM training. However, aged animals administered with hPF4 demonstrated improved learning and memory for the platform location during the testing phase of the task compared with the aged saline-treated control mice.
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Similarly, in the Nature Aging paper —

Our experiments utilized mouse PF4 (mPF4). Mouse and human PF4 share a 76% identity. To probe whether human PF4 (hPF4) also enhances cognition in mice, we treated mice with vehicle, hPF4 derived from a cell line, or human PF4 derived from human platelets. In parallel with mPF4, hPF4 from both sources also enhanced cognition in young mice. Since mPF4 and hPF4 enhanced cognition, but mouse protein may confer more robust species-specific biology in mice, we continued to conduct our experiments with mPF4.
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The Nature Comms paper comments —

Although the presence of neurogenesis in the hippocampus of adult humans has been hotly debated, the current overwhelming consensus in the field is that this process continues throughout life but declines with age, as well as in individuals with Alzheimer’s disease. Given that ageing is the most dominant risk factor for dementia related neurodegenerative diseases, it is imperative to develop novel strategies to maintain cognitive integrity in the elderly. One possibility is to harness the regenerative capacity of stem cells. Physical exercise is one of the strongest enhancers of adult hippocampal neurogenesis, and older adults who perform regular physical activity are more likely to maintain their cognitive ability. However, we still have only a limited understanding of how the systemic effects of exercise are communicated to the brain.
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It is recognised that while exercise is associated with good brain health, with co-morbidities exercise is not always possible. They are looking at what the "goodness factor" from exercise is to see if it might be synthesised and delivered without the... unnecessary sweat.
 
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