Mechanisms of abeta induced dysfunction in hippocampal neuronal circuitry

描述（由申请人提供）：突触丧失或功能障碍被认为是导致阿尔茨海默病（AD）（最常见的年龄相关性神经退行性疾病）中出现的记忆和认知缺陷的主要因素之一。根据淀粉样蛋白级联假说，假设淀粉样蛋白前体蛋白（APP）衍生的淀粉样β肽（Aβ）在脑中的逐渐积累触发导致AD的级联事件。Aβ可能引发这些事件的机制（包括突触丢失或突触功能障碍）尚不清楚。最近的研究表明，淀粉样蛋白在细胞外空间的沉积和细胞内的神经退行性变，AD的两个标志，可能以跨突触或顺行的方式进展。也就是说，AD病理学在脑中的传播（如必须随着疾病发展而发生的）以提示神经元到神经元进展的方式扩展。如果这是真的，这表明Aβ诱导的突触损伤应该是由突触前神经元启动的，以改变突触后神经元的功能。事实上，我们最近获得的初步数据支持这一概念。具体来说，只有当Aβ来自突触前神经元时，才存在突触可塑性受损，而不是相反的情况。这些新的观察结果是从转基因小鼠中获得的，这些小鼠将APP表达优先限制在海马的CA 3或CA 1神经元。因此，这些转基因小鼠提供了独特的机会来询问与脑中局部产生和释放Aβ引起的神经元功能或功能障碍相关的关键问题。这些问题不能用现有的转基因小鼠来解决，其中存在高水平的APP的泛神经元表达或最近开发的表达限于内嗅皮层的小鼠。本申请将检查产生Aβ的神经元群体对突触功能或神经元回路的损伤程度。具体来说，我们将利用转基因小鼠的空间和时间控制APP表达的神经元在CA 1，CA 3，或齿状回通过使用转基因小鼠株表达Cre重组酶在CA 1，CA 3，或齿状回颗粒细胞，分别。此外，我们将测试可逆性 这些小鼠系以及原始tTA/tet-APP系中的突触和回路功能障碍。提出了两个目标：1）我们将探索行为、生化和形态学变化是否伴随由突触前与突触后神经元释放的Aβ引发的突触可塑性损伤，以及这些功能变化是否随着年龄的增长而变得不可逆; 2）通过测量场电位和定位细胞放电模式评估这些小鼠的神经元功能障碍。总的来说，这些研究的结果使用选择性和可逆性 海马亚区APP的表达将为体内Aβ诱导的神经元功能障碍提供新的见解。

DESCRIPTION (provided by applicant): Synaptic loss or dysfunction is believed to be one of the major factors responsible for the memory and cognitive deficits seen in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. According to the amyloid cascade hypothesis, the gradual accumulation in brain of amyloid β-peptide (Aβ), derived from the amyloid precursor protein (APP), is hypothesized to trigger the cascade of events that lead to AD. The mechanisms by which Aβ may initiate these events, which include synapse loss or synaptic dysfunction, are unclear. Recent studies suggested that both amyloid deposition in extracellular space and intracellular neurofibrillary degeneration, the two hallmarks of AD, may progress in a trans-synaptic or anterograde fashion. That is, the spread of AD pathology in brain, as must occur as the disease develops, expands in a manner that is suggestive of neuron-to-neuron progression. If true, this suggests that Aβ-induced synaptic injury should be initiated by the presynaptic neuron to alter function of the postsynaptic neuron. Indeed, we have recently obtained preliminary data that support this concept. Specifically, impairment of synaptic plasticity is present only when Aβ is derived from the presynaptic neuron but not in the reverse situation. These novel observations were obtained from transgenic mice that restrict APP expression preferentially to CA3 or CA1 neurons of the hippocampus. These transgenic mice therefore provide the unique opportunity to ask key questions related to neuronal function or dysfunction caused by local production and release of Aβ in brain. These questions cannot be addressed with existing transgenic mice where there is pan-neuronal expression of APP at high levels or the recently developed mice with expression restricted to entorhinal cortex. This application will examine the degree to which injury to synaptic function or neuronal circuits develops with respect to the neuronal population where Aβ is produced. Specifically, we will utilize transgenic mice with spatial and temporal control of APP expression directed to neurons in CA1, CA3, or dentate gyrus by using transgenic mouse lines that express Cre recombinase in CA1, CA3, or dentate gyrus granule cells, respectively. In addition, we will test the reversibility of synaptic and circuit dysfunction in these mouse lines as well as in the original tTA/tet-APP line. Two Aims are proposed: 1) we will explore whether behavior, biochemical, and morphological changes accompany the impairment in synaptic plasticity initiated by Aβ released from pre- vs. postsynaptic neurons and whether these functional changes become irreversible with age and 2) assess neuronal dysfunction in these mice by measuring field potentials and place cell firing patterns. Collectively, results from these studies using selective and reversible APP expression in subregions of the hippocampus will provide fresh insights into Aβ-induced neuronal dysfunction in vivo.