Alleviating age-related memory impairment through proteasome stimulation

项目总结/摘要 衰老的特征是认知能力普遍下降，包括准确形成和回忆的能力 情景记忆糖尿病相关的记忆障碍影响了近25%的65岁以上的美国成年人， 构成阿尔茨海默病（AD）发展的重要危险因素。情感上和经济上 老龄化给照顾者、家庭和纳税人带来的负担是巨大的，而且还在不断增长， 到2050年，65岁及以上的人口将从4.1%增加到约20%。的透彻 了解导致与年龄相关的认知能力下降的神经生物学因素不仅可以提供 对衰老的机械理解，但也将为治疗提供关键途径，以尽量减少负面影响。 衰老对记忆力的影响，并降低AD的风险。衰老导致突触功能受损， 海马体，一个对记忆形成至关重要的大脑区域，以及蛋白酶体， 泛素-蛋白酶体系统（UPS）的催化成分，控制细胞中大多数蛋白质的降解。 个脑袋据报道，包括啮齿动物和哺乳动物在内的生物体的衰老组织中蛋白酶体活性降低。 人与人之间，有着千丝万缕的联系。此外，我们的小组为蛋白酶体的作用提供了强有力的证据， 活动的记忆形成，并收集了初步的数据表明，蛋白酶体的功能， 在中年动物中，在记忆障碍出现之前，这种水平已经下降了。这表明 蛋白酶体下调先于年龄相关记忆，并且可能是年龄相关记忆的主要促成因素 就像在AD中观察到的那样。然而，由于技术的限制，无论是改善这些赤字， 在蛋白酶体功能可以防止或逆转与年龄有关的记忆衰退仍然是未知的。为了解决这个 为了填补该领域的空白，我们最近开发了一种新的CRISPR-dCas9方法来持续刺激蛋白酶体 在成年动物的特定大脑区域活动。使用这种方法，本提案的目标是测试 增加海马中的蛋白酶体功能可以改善与年龄相关的记忆障碍， 相关病理生理学目的1将测试是否增加老年动物海马中的蛋白酶体活性 挽救与年龄相关的记忆缺陷，减少神经炎症，并恢复正常的学习相关 降解特异性蛋白质组目的2将测试是否增加蛋白酶体活性在海马体的年轻和 中年动物可以预防与年龄相关的记忆缺陷，神经炎症的增加， 在衰老时间点，学习相关降解特异性蛋白质组失调。总的来说，这些 结果将提供关键的洞察是否逆转蛋白酶体失调在以后的生活或预防 生命早期的蛋白酶体功能障碍可以预防或逆转与年龄相关的记忆障碍。

Project Summary/Abstract Aging is characterized by a general decline in cognitive abilities, including the ability to accurately form and recall episodic memories. Age-related memory impairments affect nearly 25% of U.S. adults over the age of 65 and constitute a significant risk factor for the development of Alzheimer's disease (AD). The emotional and financial burden of aging on caregivers, family, and taxpayers is substantial and growing, as the projected percentage of the population of individuals 65 and older will increase from 4.1% to approximately 20% by 2050. A thorough understanding of the neurobiological factors that contribute to age-related cognitive decline will not only provide a mechanistic understanding of aging, but will also provide key avenues for therapeutics to minimize the negative effects of aging on memory and reduce risk for AD. Aging results in both impaired synaptic function in the hippocampus, a brain region critical for memory formation, and reductions in activity of the proteasome, the catalytic component of the ubiquitin-proteasome system (UPS) that controls most protein degradation in the brain. Decreased proteasome activity has been reported in aged tissue across organisms, including rodents and humans, and is associated with AD. Further, our group has provided strong evidence for a role of proteasome activity in memory formation and has collected preliminary data demonstrating that proteasome function is already decreased in middle-aged animals, before memory impairments are typically present. This suggests that proteasome downregulation precedes, and is likely a major contributing factor to, age-related memory impairments like those observed in AD. However, due to technical limitations, whether ameliorating these deficits in proteasome function can prevent or reverse age-related memory decline remains unknown. To address this gap in the field, we recently developed a novel CRISPR-dCas9 approach to persistently stimulate proteasome activity in specific brain regions of adult animals. Using this approach, the goal of this proposal is to test if increasing proteasome function in the hippocampus can ameliorate age-related memory impairments and associated pathophysiology. Aim 1 will test if increasing proteasome activity in the hippocampus of aged animals rescues age-related memory deficits, reduces neuroinflammation, and restores the normal learning-related degradation-specific proteome. Aim 2 will test if increasing proteasome activity in the hippocampus of young and middle-aged animals can prevent age-related memory deficits, increases in neuroinflammation, and dysregulation of the learning-related degradation-specific proteome at aged time points. Collectively, these results will provide critical insight into whether reversing proteasome dysregulation later in life or preventing proteasome dysfunction early in life can prevent or reverse age-related memory impairment.