A Model of Early Alzheimer Disease

描述（由申请人提供）：本R21申请旨在开发和表征阿尔茨海默病（AD）研究的新模型。在阿尔茨海默病患者中，最早的神经元病变主要发生在内嗅皮层。此后，病变分层发展，包括边缘区和联合区。已知阿尔茨海默氏症中，穿孔通路（即向齿状回投射的内嗅皮层）的破坏会导致海马的失传。随着疾病的进展，这些通路和内侧颞叶密切相关的结构的破坏被认为可以解释为什么记忆障碍如此主导AD的临床症状。我们建立了一个转基因模型，利用已知对这些神经元具有特异性的tet反应启动子和tauP301L应答器，P301L tau过表达仅限于AD中最容易缠结形成的同一组星状神经元，即内皮层的第2层。这条线被称为rTauP301L EC，在EC中稳健地表达tau蛋白。这导致早期（3个月大）错误折叠的tau定位于穿孔通路及其在齿状回终末区的末端。在接下来的18个月里，突触丢失发生，一个强大的神经可塑性现象出现，乙酰氨基甲酸酯酶阳性纤维进入去传入区，形成缠结，（几个月后）神经元丢失。有趣的是，在18个月大的动物中，解剖学上连接到EC的神经元，但不表达转基因，产生tau阳性包涵体，可能来自错误折叠的内源性tau和/或错误折叠的tau蛋白突触之间的易位。第二个品系也被提出，利用新产生的野生型tau应答品系（rTg21221），完全与rTauP301L EC品系相当，但缺乏突变。我们建议从可塑性现象的角度来表征这些模型，确定在不同的点上抑制转基因是否可以防止持续的变性，并确定动物是否会出现记忆障碍的行为表型，以建立AD早期变化和进行性病理的模型。我们认为，建立早期疾病过程的模型是至关重要的，这既可以理解疾病进展的病理生理学，也可以建立一个系统来测试神经保护疗法——这是在“症状前”时间点设计干预措施的第一步，从临床角度来看，这可能是最有效的。

DESCRIPTION (provided by applicant): This R21 application proposes to develop and characterize a new model for Alzheimer disease (AD) research. In patients with AD, the earliest neuronal lesions occur primarily in the entorhinal cortex. Thereafter a hierarchical march of lesions involves limbic and association areas. Destruction of the perforant pathway, the entorhinal cortex projection to the dentate gyrus, is known to deafferent the hippocampus in AD. As the disease progresses, disruption of these pathways and closely related structures in the medial temporal lobe are believed to explain why memory impairments so dominate the clinical symptoms of AD. We have established a transgenic model in which P301L tau overexpression is limited to the same set of stellate neurons most vulnerable for tangle formation in AD, layer II of the entorhinal cortex, utilizing an established tet response promoter known to have specificity for these neurons and a tauP301L responder. This line, referred to as rTauP301L EC, expresses tau robustly in the EC. This leads to early (by 3 months of age) localization of misfolded tau in the perforant pathway and its terminals in the dentate gyrus terminal zone. Over the next 18 months, synaptic loss occurs, a robust neuroplasticity phenomenon with sprouting of AChE positive fibers into the deafferented zone occurs, tangles form, and (months later) neuronal loss ensues. Intriguingly, in animals ~18 months of age, neurons anatomically connected to the EC, but which do not express the transgene, develop tau positive inclusions, presumably from misfolded endogenous tau and/or from translocation across synapses of misfolded tau protein. A second line is proposed as well, utilizing a newly generated wild type tau responder line (rTg21221) that is entirely comparable to the rTauP301L EC line but lacks the mutation. We propose to characterize these models in terms of plasticity phenomenon, determine whether suppressing the transgene at various points can prevent ongoing degeneration, and determine whether the animals develop a behavioral phenotype of memory impairments in order to establish a model of the early changes of AD and of progressive pathology. We believe that it is critical to establish models of early disease processes to both understand the pathophysiology of progression and to generate a system in which to test neuroprotective therapies - a first step in designing interventions at a "presymptomatic" time point where they might be most effective from a clinical perspective. PUBLIC HEALTH RELEVANCE: Alzheimer disease starts with neurofibrillary lesions in a special brain area, the entorhinal cortex, which is responsible for memory related brain functions. We propose to make a model of this stage of the disease by genetically engineering a mouse to develop these same lesions in only this brain area; doing so will allow us to study the earliest phase of the disease, and to learn about whether early lesions lead to disease progression.