Abeta and Monoaminergic Neurodegeneration in Transgenic Mouse Models of AD

描述（由申请人提供）：AD的临床综合征与A？-沉积和各种神经回路和多个脑区域中的神经元群体的功能障碍/死亡。当A？产生和沉积通常被认为是必不可少的早期致病事件AD，在体内之间的关系A？和神经退化的问题还不太清楚。而转基因（Tg）小鼠模型的脑A？沉积的AD发病机制相关的研究的重要资源，这些Tg小鼠模型只表现出适度的皮质和海马神经元变性，即使有显着的A？病理因此，虽然进行性神经变性和A？-沉积是人类AD的一个关键特征，A？沉积导致的神经变性仍然是难以捉摸的。我们发现，在APPswe/PS1？E9 Tg小鼠，A？-沉积与单胺能（MA能）系统的变性有关。A？-β-肾上腺皮质和海马区的5-HT和TH+纤维均丢失。在APPswe/PS1中沉积？E9 Tg小鼠。值得注意的是，在脑干中MA能纤维的进行性变性之后是5-HT和NA神经元的变性。因此，APPswe/PS1？E9小鼠重现了在人类AD中所见的5-HT和NA系统的严重变性。这些神经元及其轴突投射的丧失在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？沉积足以引起神经变性，并允许进一步的机理分析和神经保护策略的测试。在这个建议中，我们将定义在体内的病理关系之间的A？-积累/沉积和神经变性。我们提出以下目标：1）确定发病和选择性的单胺能神经变性在APPswe/PS1？E9 Tg小鼠。2)表征tTA/APP Tg小鼠中的单胺能神经变性。3)确定大脑A之间的因果关系？单胺能神经元的产生/积累和进行性变性。4)确定tau蛋白表达与MA能神经变性之间的关系。5)确定是否单胺能神经变性（5-HT和/或NA）有助于A？APPswe/PS1中的病理学？E9 Tg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脑中淀粉样蛋白病理学和神经变性之间的病理关系。由于淀粉样蛋白病理学是AD治疗的主要靶点，并且由于AD诊断时存在持续的神经变性，因此所提出的研究将对理解AD发病机制和AD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.