Can platelets mediate adult hippocampal neurogenesis and cognitive function in the aged brain?

• Applicant: Dr. Odette Leiter
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442282648

The hippocampus of the adult brain is crucial for learning and memory. In mammals, including humans, it also represents a unique location, where adult neurogenesis occurs. During this process new neurons are generated from neural stem cells throughout life. The adult-born neurons are involved in the maintenance and improvement of cognitive abilities, highlighting the importance of this process in conditions with cognitive impairments, including physiological ageing and neurodegenerative diseases. The rate of neurogenesis can be influenced by lifestyle factors, with exercise producing a significant increase in the number of proliferating neural precursor cells in the hippocampus. However, the molecular mechanisms underlying this phenomenon are still unknown. We recently showed that platelets mediate the exercise-induced increase in adult hippocampal neurogenesis, with platelets becoming specifically activated in mice following running. Moreover, the running-induced increase in neural precursor cell proliferation was abolished in mice with a reduced number of platelets in their blood. It is still unclear how platelets communicate with the neural precursor cells due to their physical separation by the blood brain barrier, and whether the platelet-mediated increase in hippocampal neurogenesis can improve cognitive function. In this project, we will first investigate the mechanisms of platelet–neural precursor cell–interactions. We will determine whether platelets accumulate in the hippocampus close to neural precursor cells following exercise and if these brain cells engulf platelet particles. Moreover, we will determine if these interactions are mediated via the candidate protein 14-3-3 gamma, which has pro-neurogenic effects and is significantly increased in platelets following exercise. Secondly, we will investigate whether platelet treatment can increase neurogenesis and restore cognitive function in the aged mouse model, exhibiting similar hippocampus-related learning and memory impairments to those observed in elderly humans. Finally, at the host institute, we also have access to plasma samples from the participants of a clinical trial, in which the benefits of exercise on the cognitive abilities of aged humans are currently being investigated. We will determine whether the platelet-released activation marker platelet factor 4 changes following exercise. We will then correlate these measures with the results of the cognitive analyses to determine if platelet activity is associated with improvements in learning and memory in aged humans. Together these experiments will determine whether platelets comprise an endogenous reservoir that could be harnessed for the development of therapeutic interventions to promote cognitive function in ageing and disease.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Dr. Tara Walker, from 3/2020 until 2/2022