Repair and Regeneration in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是老年人中最常见的进行性痴呆类型，其特征是神经纤维缠结、反应性星形细胞增多、小胶质细胞激活和β-淀粉样肽(Abeta)的实质沉积。Aβ多肽(40-42个残基)是由淀粉样前体蛋白(APP)的结构性蛋白分解过程产生的。几条趋同的证据表明，42个残基形式的Abeta的沉积是阿尔茨海默病发病机制中的早期和关键事件。与家族性AD(FAD)相关的APP或早老素1和2(PS)的突变会改变APP的切割，使其有利于产生更长、更具淀粉样变性、42个残基的淀粉样β多肽，而不是通常更丰富的Abeta40。与每个Abeta物种比例的这种变化一起，共同表达APP和PS1的FAD变体的转基因小鼠比单独表达突变APP的小鼠更早形成Abeta沉积。因此，有相当多的遗传证据表明淀粉样蛋白沉积是阿尔茨海默病的潜在诱因之一。事实上，大多数较大的制药公司和许多较小的生物技术企业都在积极开发旨在抑制Abeta产生和/或沉积的化合物。然而，除了我们机械上不了解的一些免疫研究外，人们对哺乳动物大脑修复与淀粉样蛋白沉积相关的损伤的能力知之甚少。最近，利用JHU阿尔茨海默病研究中心的一个试点项目提供的资金，我们开发出了在四环素可以调节的启动子元件的转录控制下表达高水平突变APP的新小鼠品系。我们现在提出五个目标，以进一步开发和表征我们的新模型，然后使用这些动物来询问有关淀粉样蛋白的沉积和神经系统修复淀粉样斑块造成的损伤的能力的基本问题。在第六个目标中，我们将使用这项新技术来创造表达野生型和突变型tau的小鼠，努力制造出以可调节的方式模拟阿尔茨海默氏病的两个主要病理方面的小鼠。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common type of progressive dementia in the elderly, is characterized by neurofibrillary tangles, reactive astrocytosis, activation of microglial cells, and parenchymal deposits of beta-amyloid peptides (Abeta). The Abeta peptide (40-42 residues) is generated by the constitutive proteolytic processing of the amyloid precursor protein (APP). Several converging lines of evidence suggest that the deposition of the 42-residue form of Abeta is an early and critical event in the pathogenesis of Alzheimer's disease. Mutations in either APP, or presenilins 1 and 2 (PS), associated with familial AD (FAD) alter the cleavage of APP to favor production of the longer, more amyloidogenic, 42 residue amyloid beta peptide relative to the normally more abundant Abeta40. Together with this shift in the proportion of each Abeta species, transgenic mice co-expressing FADvariants of APP and PS1 develop Abeta deposits much earlier than mice expressing mutant APP alone. Hence, there is considerable genetic evidence to implicate amyloid deposition as one of the potential initiating insults in Alzheimer's disease. Indeed, most of the larger pharmaceutical companies and many smaller biotech enterprises are actively developing compounds that are designed to inhibit Abeta production and/or deposition. However, apart from some of the immunization studies, which we mechanistically do not understand, little is known about the capacity of mammalian brain to repair damage associated with amyloid deposition. Recently, using funds provided by a pilot project in the JHU Alzheimer's Disease Research Center, we have developed new strains of mice that express high levels of mutant APP under the transcriptional control of promoter elements that can be regulated by tetracycline. We now propose five Aims to further develop and characterize our new model and then to use these animals to ask fundamental questions regarding both the deposition of amyloid and the ability of the nervous system to repair damage caused by amyloid plaques. In a sixth Aim, we will use this new technology to create mice that express wild type and mutant tau in an effort to produce mice that model, in a regulate-able fashion, both of the major pathological aspects of Alzheimer's disease.