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

血小板可以介导老年大脑中的成人海马神经发生和认知功能吗？

• 批准号: 442282648
• 负责人: Dr. Odette Leiter
• 金额: --
• 依托单位: Queensland Brain Institute
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/442282648?language=en
• 关键词: platelets; mediate; adult; hippocampal; neurogenesis

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.

成年人大脑的海马体对学习和记忆至关重要。在包括人类在内的哺乳动物中，它也代表了一个独特的位置，在那里成年神经发生。在这个过程中，新的神经元在整个生命过程中从神经干细胞中产生。成人出生的神经元参与维持和改善认知能力，突出了这一过程在认知障碍条件下的重要性，包括生理老化和神经退行性疾病。神经发生的速度可能受到生活方式因素的影响，运动会显著增加海马体中增殖的神经前体细胞的数量。然而，这种现象背后的分子机制仍然是未知的。我们最近发现，血小板介导运动诱导的成年海马神经发生增加，血小板在小鼠跑步后被特异性激活。此外，在血液中血小板数量减少的小鼠中，跑步诱导的神经前体细胞增殖增加被消除。目前尚不清楚血小板如何与神经前体细胞沟通，因为它们被血脑屏障物理分离，以及血小板介导的海马神经发生的增加是否可以改善认知功能。在这个项目中，我们将首先研究血小板-神经前体细胞相互作用的机制。我们将确定血小板是否在运动后聚集在靠近神经前体细胞的海马体中，以及这些脑细胞是否吞噬血小板颗粒。此外，我们将确定这些相互作用是否是通过候选蛋白14-3-3 γ介导的，该蛋白具有促神经原性作用，并且在运动后血小板中显著增加。其次，我们将研究血小板治疗是否可以增加老年小鼠模型中的神经发生和恢复认知功能，表现出与老年人中观察到的相似的海马区相关的学习和记忆障碍。最后，在主办机构，我们还可以获得临床试验参与者的血浆样本，目前正在研究运动对老年人认知能力的益处。我们将确定运动后血小板释放的活化标志物血小板因子4是否发生变化。然后，我们将这些措施与认知分析的结果相关联，以确定血小板活性是否与老年人学习和记忆的改善有关。这些实验将共同确定血小板是否包含一个内源性储库，可以用于开发治疗干预措施，以促进衰老和疾病的认知功能。