Mechanisms of abeta induced dysfunction in hippocampal neuronal circuitry

描述(由申请人提供)：突触丢失或功能障碍被认为是导致阿尔茨海默病(AD)记忆和认知障碍的主要因素之一，阿尔茨海默病(AD)是最常见的年龄相关性神经退行性疾病。根据淀粉样蛋白级联假说，淀粉样前体蛋白(APP)衍生的淀粉样多肽(A？)在大脑中的逐渐积聚被假设为触发了导致AD的一系列事件。A？引发这些事件的机制尚不清楚，这些事件包括突触丢失或突触功能障碍。最近的研究表明，阿尔茨海默病的两个特征，即细胞外空间淀粉样蛋白沉积和细胞内神经纤维变性，都可能以跨突触或顺行的方式进展。也就是说，随着疾病的发展，AD病理在大脑中的传播必须以一种暗示神经元向神经元进展的方式扩展。如果这是真的，这表明A？诱导的突触损伤应该由突触前神经元启动，以改变突触后神经元的功能。事实上，我们最近获得了支持这一概念的初步数据。具体地说，只有当A来自突触前神经元时，突触可塑性才会受到损害，而不是在相反的情况下。这些新的观察结果来自转基因小鼠，它们将APP的表达限制在海马区的CA3或CA1神经元上。因此，这些转基因小鼠提供了一个独特的机会，可以提出与大脑中局部产生和释放A？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，因为在现有的转基因小鼠中，APP的泛神经元表达水平很高，或者最近开发的小鼠的表达仅限于内嗅皮层。这项应用将检查突触功能或神经元回路损伤的程度相对于产生A？的神经元群体。具体地说，我们将利用分别在CA1、CA3或齿状回颗粒细胞中表达Cre重组酶的转基因小鼠，利用针对CA1、CA3或齿状回神经元的APP表达的空间和时间控制的转基因小鼠。此外，我们还将测试可逆性 在这些小鼠品系以及最初的TTA/tet-app品系中，突触和回路功能障碍。我们提出了两个目标：1)我们将探索行为、生化和形态变化是否伴随着突触前和突触后神经元释放的A？引发的突触可塑性损害，以及这些功能变化是否随着年龄的增长而不可逆转；2)通过测量场电位和定位细胞放电模式来评估这些小鼠的神经元功能障碍。总的来说，这些研究的结果是使用选择性和可逆性的 APP在海马亚区的表达将为体内A？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 ¿-peptide (A¿), derived from the amyloid precursor protein (APP), is hypothesized to trigger the cascade of events that lead to AD. The mechanisms by which A¿ 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 A¿-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 A¿ 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 A¿ 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 A¿ 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 A¿ 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 A¿-induced neuronal dysfunction in vivo.