Circulatory Rejuvenating Factors for the Brain

描述(申请人提供)：人类的认知功能从50-60岁左右开始几乎在所有领域都会下降，神经退行性变和痴呆症似乎在所有活到很老的人中都是不可避免的，除了少数人。小鼠的寿命只有人类的一小部分 表现出类似的认知退化，表明特定的生物过程而不是时间 导致大脑老化的因素只有一个。虽然与年龄相关的认知功能障碍和痴呆在人类中是明显不同的实体，并影响不同的大脑区域，但老化的大脑显示出具有大多数神经退行性疾病特征的分子和细胞变化，包括突触丢失、自噬功能障碍、炎症增加和蛋白质聚集。值得注意的是，老化的大脑仍然是可塑性的，运动或饮食变化可以提高人类和动物的认知功能，动物的大脑显示出上述与衰老相关的一些生物学变化的逆转。利用异慢性异生现象，我们最近表明，存在于全身环境中的血液传播因子可以抑制或促进成年小鼠的神经发生，这种方式与年龄有关。因此，将老年小鼠暴露在年轻的全身环境中或暴露于年轻小鼠的血浆中会增加神经发生、突触可塑性，并改善背景恐惧条件反射以及空间学习和记忆。初步的蛋白质组学研究表明，几种具有干细胞活性的蛋白质在老年“恢复活力”的小鼠中增加，支持年轻血液可能含有更多具有再生能力的有益因子的概念。在本应用程序中，我们打算 检验幼鼠血液中的蛋白质因子足以增加成年鼠的假说 神经发生和旧脑再生，而聚焦蛋白质组筛查将使我们能够识别最有效的这类因素。我们的研究追求一个创新的概念，即大脑老化和认知功能障碍至少部分受循环环境因素的控制，这些因素足以使老化的大脑恢复活力。

DESCRIPTION (provided by applicant): Cognitive function in humans declines in essentially all domains starting around age 50-60, and neurodegeneration and dementia seem to be inevitable in all but a few who survive to very old age. Mice with a fraction of the human lifespan show similar cognitive deterioration indicating that specific biological processes rather than time alone are responsible for brain aging. While age-related cognitive dysfunction and dementia in humans are clearly distinct entities and affect different brain regions, the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases including synaptic loss, dysfunctional autophagy, increased inflammation, and protein aggregation. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals, with animal brains showing a reversal of some of the aforementioned biological changes associated with aging. Using heterochronic parabiosis we showed recently that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Preliminary proteomic studies show several proteins with stem cell activity increase in old "rejuvenated" mice supporting the notion that young blood may contain increased levels of beneficial factors with regenerative capacity. In this application we intend to test the hypothesis that blood-borne protein factors in young mice are sufficient to increase adult neurogenesis and regenerate the old brain, and that a focused proteomic screen will allow us to identify the most potent such factors. Our studies pursue the innovative concept that brain aging and cognitive dysfunction is at least in part under control of factors from the circulatory environment and that such factors are sufficient to rejuvenate the aging brain.