Memory and ProBDNF Processing in the Aged Mouse Hippocampus

描述（由申请人提供）：与年龄相关的认知能力下降是60岁及以上人群的常见病，患病率估计为20-27%，对于识别痴呆的临床前阶段有很高的用途。记忆任务的缺陷通常与海马体和投射到海马体和皮层的胆碱能神经元功能障碍有关。虽然目前神经变性和认知缺陷的治疗主要集中在氧化应激和支持乙酰胆碱神经传递的神经保护上，但本项目提出了一种改变范式的方法，即前神经营养素的蛋白水解加工。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，并可能在预防衰老相关的变性中发挥重要作用。我们将从行为学、药理学、生物化学和神经解剖学等多个层面研究proBDNF在衰老相关记忆障碍海马神经元功能障碍中的作用。我们将研究老年和年轻小鼠海马中的proBDNF加工，并评估行为任务中BDNF信号传导与记忆缺陷之间的相关性。我们还将从药理学上操纵proBDNF加工，以改善老年动物的记忆表现。如果这项研究取得成功，它将通过确定一套新的靶向治疗分子途径，影响未来旨在保护老年人记忆表现的治疗方法。

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. PUBLIC HEALTH RELEVANCE: 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. Our studies will investigate a molecular pathway to be targeted by future therapies aimed at preserving memory performance in aged individuals.