Protein Injection Replicates Exercise Benefits in Mouse Brain

Brain boost from exercise

Regular physical activity can support human health and wellbeing by increasing muscle mass and strength, promoting healthier bones, reducing disease susceptibility and lowering mortality risk. More recently, science has demonstrated that exercise can elicit positive effects in the brain, potentially counteracting cognitive decline that occurs during aging and neurodegenerative diseases.

Exercise is not accessible to everyone, however. Health conditions, physical disabilities and the burden of an aging body can limit a person’s mobility levels. Can these populations still reap the positive cognitive effects of exercise? It’s a million-dollar question, literally – commercial interest in “exercise pills”, drugs that can provide the molecular benefits of exercise artificially, continues to grow.

“We know exercise increases production of new neurons in the hippocampus, the part of the brain important for learning and memory, but the mechanism hasn’t been clear,” Dr. Odette Leiter, a postdoctoral research fellow at the Queensland Brain Institute at the University of Queensland (UQ), says.

Leiter and Dr. Tara Walker, also a research fellow at the Queensland Brain Institute at UQ led a new study, published in Nature Communications, that sheds light on this mechanism.

Platelet protein production – induced by exercise – enhances neurogenesis

In 2019, Leiter, Walker and colleagues published a study – conducted in mice – which revealed an “unexpected” role of platelets in mediating exercise-induced increases in hippocampal neurogenesis. “We found that platelets are activated by acute exercise and release humoral factors including the chemokine platelet factor 4 (PF4). We also showed that PF4 is sufficient to enhance hippocampal neurogenesis when delivered directly to the brain of young mice via osmotic pumps,” the researchers explain.

In the new study, the researchers wanted to explore whether PF4 can replicate the beneficial effects of exercise on neurogenesis in aging mice.

In transgenic models of aging mice, Leiter and colleagues systemically administered P4F via the tail vein. “We discovered that the exerkine CXCL4/platelet factor 4 or PF4, which is released from platelets after exercise, results in regenerative and cognitive improvements when injected into aged mice,” Leiter says. “We can now target platelets to promote neurogenesis, enhance cognition and counteract age-related cognitive decline.”

Neural stem cells in a mouse hippocampus shown in green (cell bodies shown in blue) give rise to new mature neurons. Credit: The authors.

Based on the encouraging preclinical data, Leiter and Walker plan to test the response of PF4 injection in mouse models of Alzheimer’s disease. After that, they have their sights on human clinical trials. “For a lot of people with health conditions, mobility issues or of advanced age, exercise isn’t possible, so pharmacological intervention is an important area of research,” Walker says, though she adds, “It’s important to note this is not a replacement for exercise.”

Reference: Leiter O, Brici D, Fletcher SJ, et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat Comms. 2023;14(1):4375. doi: 10.1038/s41467-023-39873-9

This article is a rework of a press release issued by the Queensland Brain Institute at the University of Queensland. Material has been edited for length and content.