Mechanisms of Synaptic Aging Mediating Cognitive and Behavioral Symptoms of AD

总结 阿尔茨海默病（Alzheimer's disease，AD）是一种复杂的神经退行性疾病，表现为渐进性的， Aβ肽和过度磷酸化tau（ptau）的积累。唯一最重要的因素是老化。 然而，介导衰老相关风险的机制尚未得到很好的理解。突触结构丧失 和功能标志着AD的早期阶段，可能比临床症状早几十年。这意味着 与衰老有关的风险机制可能在中年时已经开始发挥作用。明确测试此类 在AD小鼠模型中的衰老机制一直是有问题的，因为在常规模型中， 都离不开病理学的影响为了应对这一挑战，我们 可诱导模型，其可以有条件地延迟tau和/或APP的表达直到成年早期、中期或老年 年龄我们发现，中年发病的APP小鼠，其模型开始在人类淀粉样变性，在第四， 10年寿命的小鼠比10年寿命的小鼠出现更严重的认知缺陷，并且处于Aβ积累的早期阶段。 一个成年早期的发病。在这里，我们将进一步利用这些条件模型来搜索分子 年龄脆弱性背后的机制。作为分析的一部分，我们将探讨一个 候选基因通路，NPTX 2，这是第一次涉及我们的研究人类AD。初步研究 小鼠模型显示，在中年和老年，而不是年轻时，NPTX 2依赖于ApoA下调 成年老鼠因此，我们假设NPTX 2代表了一种衰老敏感性途径， 人类AD的病理生理学。在目标1中，我们将使用不同发病年龄的诱导型转基因小鼠 APP和/或tau表达（成年、中年或老年），以测试单独的tau或与 Ablation导致NPTX 2表达减少。在目标2中，我们将筛选衰老和Ablast/tau相关 通过定量质谱法测定突触蛋白表达的变化。验证NPTX 2中的更改， 其它突触蛋白将用于确认MS分析的灵敏度。在目标3中，我们将测试年龄是否- NPTX 2的相关下调有助于认知表型。目标4将评估老龄化的作用， 抑郁症表型中的Akt/tau和NPTX 2。目标5将解决老龄化过程中可能存在的性别差异- 相关的认知和抑郁表型。本提案中计划的研究旨在 描述NPTX 2依赖性通路在进行性衰老和AD背景下的功能和调节 并将有助于揭示认知和行为的分子基础和治疗方向 AD的症状

SUMMARY Alzheimer's disease (AD) is a complex cascade of neurodegenerative processes that expressed as gradual accumulation of Aβ peptides and hyperphosphorylated tau (ptau). The single most important factor is aging. However, mechanisms that mediate aging-associated risks are not well understood. Loss of synaptic structure and function marks early stages of AD that may precede clinical symptoms by decades. This implies that mechanisms of aging-related risks might be at work already by middle age. Explicit testing of such mechanisms in AD mouse models has been problematic, since in conventional models the effects of aging cannot be separated from the effects of advanced pathology. To address this challenge, we have employed inducible models that can conditionally delay expression of tau and/or APP until early adulthood, middle, or old age. We find that middle-age onset APP mice, which model initiation of amyloidosis in humans in the 4th decade of life develop more severe cognitive deficits and at earlier stages of Aβ accumulation than mice with an early-adulthood onset. Here, we will further employ these conditional models to search for molecular mechanisms that underlie age vulnerability. As part of this analysis we will explore the contribution of a candidate gene pathway, NPTX2, which was first implicated in our studies of human AD. Preliminary studies in mouse models demonstrate Aß dependent down-regulation of NPTX2 in middle and old age but not young adult mice. Accordingly, we hypothesize that NPTX2 represents an aging-sensitive pathway that is relevant to the pathophysiology of human AD. In Aim 1, we will use inducible transgenic mice with different ages of onset of APP and/or tau expression (young-adult, middle- or old-age) to test whether tau alone or in combination with Aß causes a reduction of NPTX2 expression. In Aim 2, we will screen for aging and Aß/tau associated changes in synaptic protein expression by quantitative mass spectrometry. Verified changes in NPTX2 and other synaptic proteins will be used to confirm sensitivity of MS analyses. In Aim 3, we will test whether age- associated downregulation of NPTX2 contributes to cognitive phenotypes. Aim 4 will assess the role of aging, Aß/tau and NPTX2 in depression phenotypes. Aim 5 will address possible sex-related differences in the aging- associated cognitive and depressive phenotypes. The studies planned in this proposal are designed to delineate the function and regulation of NPTX2-dependent pathways in a setting of progressive aging and AD pathologies and will help to reveal the molecular basis and therapeutic directions for cognitive and behavioral symptoms of AD.