Mechanisms of Synaptic Aging Mediating Cognitive and Behavioral Symptoms of AD

摘要 阿尔茨海默病(AD)是一系列复杂的神经变性过程，表现为渐进性 Aβ多肽和过度磷酸化tau(Ptau)的积累。其中最重要的一个因素就是衰老。 然而，调节衰老相关风险的机制还没有被很好地理解。突触结构丧失 而功能标志着AD的早期阶段，可能比临床症状早几十年。这意味着 到中年时，与衰老相关的风险机制可能已经开始发挥作用。明确测试这样的 AD小鼠模型的机制一直存在问题，因为在传统模型中，衰老的影响 离不开高级病理学的影响。为了应对这一挑战，我们聘请了 诱导型模型，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。我们发现中年起病的APP小鼠，在第4天建立了人类淀粉样变性的模型 寿命十年的小鼠出现更严重的认知缺陷，并在Aβ积累的早期阶段 一种早熟症状。在这里，我们将进一步使用这些条件模型来搜索分子 造成年龄脆弱性的机制。作为本分析的一部分，我们将探讨 候选基因途径，NPTX2，这是我们在人类AD研究中首次发现的。中国的初步研究 小鼠模型显示NPTX2在中老年呈依赖的下调，但在年轻时不存在 成年小鼠。因此，我们假设NPTX2代表一个与衰老相关的敏感途径。 人类阿尔茨海默病的病理生理学。在目标1中，我们将使用不同发病年龄的可诱导转基因小鼠。 APP和/或tau的表达(年轻人、中年人或老年人)，以测试tau是单独还是与 A？可降低NPTX2的表达。在目标2中，我们将筛查年龄和A？/tau相关 定量质谱仪检测突触蛋白表达的变化。已验证NPTX2和 其他突触蛋白将用于确认MS分析的敏感性。在目标3中，我们将测试年龄是否- NPTX2的相关下调有助于认知表型。目标4将评估衰老的作用， Aü/tau和NPTX2在抑郁症表型中的作用目标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。本提案中计划进行的研究旨在 NPTX2依赖通路在进行性衰老和阿尔茨海默病中的作用和调节 有助于揭示认知和行为障碍的分子基础和治疗方向 阿尔茨海默病症状。

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.