Mechanisms of AB-induced Neuronal Deficits

在“衰老中枢神经系统的蛋白质病”的总体主题中，项目5 专注于阿尔茨海默病（AD）。我们在上一个资助期间获得的见解和 AD对公众健康构成的威胁不断增加，促使我们在当前保持这一关注。 提议我们还将继续利用神经元表达人淀粉样蛋白的转基因小鼠 前体蛋白（hAPP）和淀粉样蛋白-p（A（3）肽，因为有大量证据表明， 这些模型和人类状况之间的机械信息重叠。在我们最初的 应用，我们承诺阐明的过程中，Ap elderly神经元的缺陷。我们发现 在齿状回和内嗅皮层的神经元受到AD的早期和严重影响， 特别容易受到A| 3-诱导的蛋白质消耗，这是关键的学习和记忆。 鉴定了几种可能介导这一过程的分子。我们还确定了预防A| 3- 在hAPP小鼠中诱导神经元缺陷。例如，tau蛋白的减少有效地阻止了A（3- 依赖性记忆缺陷和分子神经元改变。尽管这背后的机制 然而，我们已经知道，它并不依赖于A（3）的变化， 水平或沉积。相反，tau蛋白的减少似乎可以防止神经元网络的异常增加。 兴奋性我们的新建议是建立在我们在前一次会议上获得的最有希望的发现的基础上的。 融资期。在目标1中，我们将检查A是否|3直接或间接影响脆弱的神经元， 这些神经元接收兴奋性输入的其他区域的变化。在目标2中，我们将确定 调节兴奋性毒性相关的神经元或神经胶质分子可以阻断AP诱导的神经元凋亡， 过度兴奋，消除异常的网络活动，并改善hAPP小鼠的行为异常。 在目标3中，我们将评估tau蛋白减少是否也可以预防神经元缺陷的小鼠模型。 帕金森病和亨廷顿病。证实这些未经检验的假设应该会有所帮助 阐明A的机制|3-依赖性认知缺陷，并铺平道路， 开发更好的治疗AD和其他神经系统疾病的方法。拟议的研究包括 与所有其他项目负责人进行协作互动，并依赖所有四个核心的支持。的 我们将在这个项目中获得的机械和治疗见解应该有助于回答一些关键问题， 这将有助于解决其他项目中的问题，从而使整个方案受益。

Within the overarching theme of "Proteinopathies of the Aging Central Nervous System," Project 5 has focused on Alzheimer's disease (AD). The insights we gained during the preceding funding period and the ever increasing threat AD poses to public health have motivated us to maintain this focus in the current proposal. We will also continue to utilize transgenic mice with neuronal expression of human amyloid precursor proteins (hAPP) and amyloid-p (A(3) peptides, because there is substantial evidence for mechanistically informative overlap between these models and the human condition. In our original application, we promised to shed light on the processes by which Ap elicits neuronal deficits. We found that neurons in the dentate gyrus and entorhinal cortex¿brain regions affected early and severely by AD¿are particularly vulnerable to the A|3-induced depletion of proteins that are critical for learning and memory. Several molecules were identified that may mediate this process. We also identified strategies to prevent A|3- induced neuronal deficits in hAPP mice. For example, reduction of the tau protein effectively prevented A(3- dependent memory deficits and molecular neuronal alterations. Although the mechanism underlying this striking rescue remains to be fully elucidated, we already know that it does not depend on changes in A(3 levels or deposition. Rather, tau reduction appears to prevent aberrant increases in neuronal network excitability. Our new proposal builds on the most promising findings we obtained during the preceding funding period. In Aim 1, we will examine whether A|3 affects vulnerable neurons directly or indirectly through changes in other regions from which these neurons receive excitatory inputs. In Aim 2, we will determine if the modulation of excitotoxicity-related neuronal or glial molecules can block Ap-induced neuronal overexcitation, eliminate aberrant network activities, and ameliorate behavioral abnormalities in hAPP mice. In Aim 3, we will assess whether tau reduction can prevent neuronal deficits also in mouse models of Parkinson's disease and Huntington's disease. Confirmation of these untested hypotheses should help elucidate the mechanisms that underlie A|3-dependent cognitive deficits and pave the way for the development of better treatments for AD and other neurological disorders. The proposed studies involve collaborative interactions with all other project leaders and depend on support from all four cores. The mechanistic and therapeutic insights we will gain in this project should help answer some of the key questions pursued in the other projects and, thus, will benefit the program as a whole.