Abeta and Monoaminergic Neurodegeneration in Transgenic Mouse Models of AD

描述（由申请人提供）：AD临床综合征与A？-各种神经回路和多个脑区神经元群的沉积和功能障碍/死亡。而一个?-的产生和沉积被普遍认为是AD早期必不可少的致病事件，体内A？神经退行性变还没有被很好地理解。而转基因（Tg）小鼠脑A？沉积是研究AD发病机制的重要资源，这些Tg小鼠模型仅表现出中度皮质和海马神经元变性，即使A？病理。因此，进行性神经变性和A？-沉积是人类AD的一个关键特征，a ？-沉积导致神经退行性变的原因尚不清楚。我们发现在APPswe/PS1？E9 Tg小鼠，A？-沉积与单胺（MAergic）系统退化有关。5-羟色胺和TH+纤维在A？-在APPswe/PS1中的沉积？e9tg小鼠。值得注意的是，脑干中5-HT和NA神经元的退化伴随着魔幻纤维的进行性变性。因此,APPswe / PS1吗?E9小鼠再现了人类AD中5-HT和NA系统的严重退化。这些神经元及其各自的轴突突起的丧失在ad相关的学习、记忆和情感功能障碍中起着重要作用。我们的发现表明A？-沉积足以引起神经退行性变，并允许进一步的机制分析和测试神经保护策略。在本提案中，我们将定义A？-积聚/沉积和神经变性。我们提出以下目标：1)确定APPswe/PS1的单胺能神经变性的发病和选择性？e9tg小鼠。2) tTA/APP Tg小鼠单胺神经变性特征。3)确定大脑A之间的因果关系？单胺神经元的产生/积累和进行性变性。4)确定tau表达与MAergic神经变性的关系。5)确定单胺能性神经变性（5- ht和/或NA）是否有助于A的进展？APPswe/PS1？e9tg小鼠。公共卫生相关性：虽然淀粉样蛋白病理和神经变性是阿尔茨海默病（AD）的关键特征，但淀粉样蛋白病理和神经变性之间的病理关系目前尚不清楚。我们将利用我们在AD转基因小鼠模型中新发现的单胺能神经元的神经变性来确定淀粉样蛋白病理与脑神经变性之间的病理关系。由于淀粉样蛋白病理是阿尔茨海默病治疗的主要目标，并且在阿尔茨海默病诊断时存在持续的神经退行性变，因此所提出的研究将对了解阿尔茨海默病的发病机制和阿尔茨海默病的治疗方法产生重大影响。

DESCRIPTION (provided by applicant): The clinical syndrome of AD is associated with A?-deposition and the dysfunction/death of populations of neurons in a variety of neural circuits and in multiple brain regions. While A?-production and deposition are generally thought to be essential early pathogenic events AD, in vivo relationship between A? and neurodegeneration is not well understood. While transgenic (Tg) mouse models of cerebral A? deposition have been important resources for studies relevant to AD pathogenesis, these Tg mouse models only exhibit modest degeneration of cortical and hippocampal neurons even with significant A? pathology. Thus, while progressive neurodegeneration and A?-deposition is a key feature of AD in humans, the in vivo mechanisms by which A?-deposition cause neurodegeneration remain elusive. We found that, in the APPswe/PS1?E9 Tg mice, A?-deposition is associated with degeneration of monoaminergic (MAergic) systems. Both 5-HT and TH+ fibers are lost from cortical and hippocampal regions with A?-deposition in the APPswe/PS1?E9 Tg mice. Significantly, progressive degeneration of MAergic fibers is followed by the degeneration of 5-HT and NA neurons in the brain stem. Thus, APPswe/PS1?E9 mice recapitulate the profound degeneration of 5-HT and NA systems seen in human AD. The loss of these neurons and their respective axonal projections play significant roles in AD-associated dysfunctions related to learning, memory, and affect. Our finding show that A?-deposition is sufficient to cause neurodegeneration and allows for further mechanistic analysis and testing of neuroprotective strategies. In this proposal, we will define in vivo pathologic relationship between A?- accumulation/deposition and neurodegeneration. We propose the following aims: 1) Determine the onset and selectivity of monoaminergic neurodegeneration in APPswe/PS1?E9 Tg mice. 2) Characterize monoaminergic neurodegeneration in the tTA/APP Tg mice. 3) Determine the causal relationship between brain A? production/accumulation and progressive degeneration of monoaminergic neurons. 4) Determine the relationship between tau expression and MAergic neurodegeneration. 5) Determine if the monoaminergic neurodegeneration (5-HT and/or NA) contributes to progression of A? pathology in APPswe/PS1?E9 Tg mice. PUBLIC HEALTH RELEVANCE: While amyloid pathology and neurodegeneration are key features of Alzheimer's Disease (AD), pathologic relationship between amyloid pathology and neurodegeneration is currently unclear. We will exploit our newly found neurodegeneration of monoaminergic neurons in transgenic mouse models of AD to determine the pathologic relationships between amyloid pathology and neurodegeneration in brain. Since amyloid pathology is a major target of AD therapeutics and because there is an ongoing neurodegeneration at diagnosis of AD, the proposed studies will have significant impact on understanding AD pathogenesis and on therapeutic approaches for AD.