Testing a new hypothesis for CNS synaptic senescence

 描述（由申请人提供）：认知功能下降已成为老年人最大的健康威胁之一。正常衰老期间认知功能的下降是 这被认为是由于突触功能障碍而不是突触或神经元的丢失。虽然负责的机制还不清楚，但突触周转率在老年大脑中降低，这表明衰老的突触随着年龄的增长而积累，导致认知能力下降，并使大脑处于与年龄相关的神经退行性疾病（如阿尔茨海默病）的较高风险中。在这个项目中，我们建议调查的细胞和分子机制，突触衰老的正常中枢神经系统老化的基础。具体来说，我们假设，星形胶质细胞，一个主要类别的中枢神经系统胶质细胞，是关键介质的突触健康在老化过程中。最近，我们发现星形胶质细胞在发育和成年大脑中积极吞噬和消除突触。随着正常老化，星形胶质细胞似乎逐渐吞噬更少的突触。我们将专门研究这一假设，即随着年龄的增长，星形胶质细胞的突触周转减少可能导致衰老突触的指数积累和认知能力下降，增强这种周转机制可以防止或最大限度地减少突触衰老。首先，我们将在大脑的生命周期内描述星形胶质细胞体内突触吞噬的速率，以证实这种吞噬速率随着正常衰老而逐渐下降，并确定星形胶质细胞是否优先消除不同的突触类型或特定神经回路中的突触。其次，我们将通过遗传分析和纯化的哺乳动物星形胶质细胞体外试验来确定星形胶质细胞吞噬突触下降的分子和细胞机制。最后，我们将培育出一种增强星形胶质细胞吞噬突触的转基因小鼠，以确定“加速”星形胶质细胞吞噬突触是否会改善衰老过程中的认知能力。这些实验有可能导致更好地理解为什么突触衰老发生在衰老的大脑中，并导致新的疗法来减轻认知能力下降和对阿尔茨海默氏症和其他神经退行性疾病的脆弱性。

 DESCRIPTION (provided by applicant): The decline of cognitive function has emerged as one of the greatest health threats of old age. The decline of cognitive function during normal aging is thought to be due to synaptic malfunction rather than loss of synapses or neurons. Although the mechanisms responsible are as yet unknown, the rate of synapse turnover is reduced in the aged brain, suggesting that senescent synapses accumulate with aging contributing to cognitive decline and placing the brain at higher risk for age-associated neurodegenerative diseases such as Alzheimer's disease. In this project, we propose to investigate the cellular and molecular mechanisms that underlie synaptic senescence of normal CNS aging. Specifically, we hypothesize that astrocytes, a major class of central nervous system glia, are critical mediators of synaptic health during aging. Recently, we discovered that astrocytes actively engulf and eliminate synapses in the developing and adult brain. Astrocytes appear to progressively engulf fewer synapses with normal aging. We will specifically investigate the hypothesis that reduced synaptic turnover by astrocytes with aging could lead to exponential accumulation of senescent synapses and cognitive decline and that enhancing this turnover mechanism could prevent or minimize synaptic senescence. First, we will characterize the rate of synapse engulfment by astrocytes in vivo over the lifetime of the brain to confirm that this engulfment rate progressivel declines with normal aging, and also determine whether astrocytes preferentially eliminate different synapse types or synapses in specific neural circuits. Second we will determine the molecular and cellular mechanisms that underlie this decline in engulfment of synapses by astrocytes by genetic profiling and in vitro assays with purified mammalian astrocytes. Finally, we will generate a transgenic mouse that has enhanced astrocyte phagocytosis of synapses to find out whether "speeding up" astrocyte synapse eating improves cognition during aging. These experiments have the potential to lead to a better understanding of why synaptic senescence occurs in the aging brain, and to lead to new therapies to lessen cognitive decline and vulnerability to Alzheimer's and other neurodegenerative diseases.