Memory and ProBDNF Processing in the Aged Mouse Hippocampus

描述(申请人提供)：与年龄相关的认知衰退是60岁及以上人群中的一种常见情况，患病率估计为20%-27%，对于识别痴呆症的临床前阶段非常有用。记忆任务的缺陷通常与海马体功能障碍以及投射到海马体和皮质的胆碱能神经元有关。虽然目前治疗神经退行性变和认知障碍的方法主要集中在保护神经免受氧化应激和支持乙酰胆碱的神经传递上，但该项目提出了一种改变范式，转向对前神经营养素的蛋白质分解过程。神经营养因子及其前体之间的平衡调节着发育和成人大脑中至关重要的过程，包括神经元存活、突触发生和突触可塑性，并可能在防止衰老相关的退化中发挥重要作用。我们将从行为学、药理学、生物化学和神经解剖学等多层次的角度研究proBDNF在衰老相关记忆损伤的海马神经元功能障碍中的作用。我们将研究ProBDNF在老年和年轻小鼠海马区的处理，并将在行为任务中评估BDNF信号与记忆缺陷之间的相关性。我们还将对proBDNF的处理进行药理学操作，以改善老年动物的记忆能力。如果这项研究成功，它将影响未来的治疗，旨在通过确定一组新的分子通路作为治疗的靶点，以保存老年人的记忆能力。

DESCRIPTION (provided by applicant): Aging-associated cognitive decline is a frequent condition among individuals aged 60 and over, with prevalence estimated at 20-27%, and is of high use for the identification of preclinical stages of dementia. Deficits in memory tasks are often related to dysfunctions of the hippocampus and cholinergic neurons projecting to the hippocampus and cortex. While present therapies for neurodegeneration and cognitive deficits are focused on neuroprotection from oxidative stress and supporting acetylcholine neurotransmission, this project proposes a change of paradigm towards proteolytic processing of pro-neurotrophins. The balance between neurotrophins and their precursors regulates critically important processes in developing and adult brains, including neuronal survival, synaptogenesis and synaptic plasticity, and may play important roles in preventing aging-related degeneration. We will study the role of proBDNF in hippocampal neuron dysfunctions underlying aging-related memory impairment using a multilevel approach: behavioral, pharmacological, biochemical and neuroanatomical. We will investigate proBDNF processing in the aged versus young mouse hippocampus, and we will evaluate correlations between BDNF signaling and memory deficits in a behavioral task. We will also pharmacologically manipulate proBDNF processing in order to improve memory performance in aged animals. Should this study be successful, it would impact future therapies aimed at preserving memory performance in aged individuals by identifying a new set of molecular pathways to be targeted by therapy.