Abeta and Monoaminergic Neurodegeneration in Transgenic Mouse Models of AD

描述(申请人提供)：阿尔茨海默病的临床综合征与A？-沉积和各种神经回路和多个大脑区域的神经元群体的功能障碍/死亡有关。虽然A？-的产生和沉积通常被认为是AD的早期致病事件中必不可少的，但在体内A？神经退行性变还没有得到很好的理解。而转基因(TG)小鼠模型脑A？沉积已成为AD发病机制相关研究的重要资源，这些TG小鼠模型仅表现出皮质和海马神经元的轻度变性，即使A？病理学。因此，虽然进行性神经变性和A？沉积是人类阿尔茨海默病的一个关键特征，但A？沉积导致神经变性的体内机制仍然难以捉摸。我们发现，在APPswe/PS1、E9TG小鼠中，A？-沉积与单胺能系统的退化有关。APPsWE/PS1、E9TG小鼠皮质和海马区均有5-羟色胺和TH+纤维丢失，并伴有A？-沉积。值得注意的是，MA能纤维进行性变性之后，脑干中的5-羟色胺和去甲肾上腺素神经元也随之退化。因此，APPswe/PS1？E9小鼠概括了在人类AD中看到的5-羟色胺和NA系统的深刻退化。这些神经元及其各自轴突投射的丢失在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？-沉积足以导致神经退行性变，并允许进一步的机制分析和神经保护策略的测试。在这项提案中，我们将在体内定义A？-堆积/沉积与神经退行性变之间的病理关系。1)研究APPsWE/PS1、E9TG小鼠单胺能神经退行性变的发生和选择性。2)TTA/APP TG小鼠单胺能神经变性的特征。3)确定A脑与A脑之间的因果关系。单胺能神经元的产生/积聚和进行性变性。4)确定tau蛋白表达与大脑皮质能神经退行性变的关系。5)确定单胺能神经变性(5-羟色胺和/或去甲肾上腺素)是否参与A？APPsWE/PS1、E9TG小鼠的病理变化。

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.