Genetics models of human dementias

痴呆症是影响老年人的最使人衰弱的疾病之一。大多数病例是由阿尔茨海默病（AD）引起的，其特征是老年斑、神经原纤维缠结和突触丧失。尽管这些疾病在老年人群中的发病率迅速增加，但由于缺乏合适的动物模型，在了解这些疾病的病因和发病机制以及开发治疗方法方面的进展受到严重阻碍。此外，微血管疾病在老年大脑中是一种常见的发现，它可能先于痴呆的发展。ApoE4基因是多种血管病变的易感因素，也是散发性AD发生的重要危险因素。常染色体显性遗传病CADASIL是由Notch3基因突变引起的，是一种脑微血管疾病，可导致中风和痴呆，其特征是脑小动脉平滑肌层增厚。Agrin是外周神经系统的一种突触组织分子，在正常大脑中有表达，但其功能尚不清楚。在中枢神经系统中，它既存在于神经元中，也存在于构成血脑屏障的毛细血管基底膜中。该项目的两位成员（Fallon和Stopa）最近的研究表明，agin重新分配到含有abeta的老年性斑块，并在AD大脑中变得不溶性。这些患者还表现出脑微血管的包膜基底膜破裂。在本提案中，我们将使用组织特异性靶向破坏agrin基因作为研究正常大脑（目标1）和AD小鼠模型（目标2）突触中agrin功能的工具。我们还将研究AD小鼠模型以及ApoE4纯合子动物的微血管状态，特别是关于基底膜中的agrin表达。最后，我们将通过“敲入”突变的Notch3等位基因来生成CADASIL小鼠模型（Aim #3）。我们将描述这些动物的微血管特征，并与CADASIL患者进行比较。我们还将确定具有CADASIL表型的MRI证据的患者中显性Notch3突变的患病率。

Dementia is among the most debilitating disorders affecting the elderly. The majority of cases are caused by Alzheimer's disease (AD), which is characterized by senile plaques, neurofibrillary tangles, and loss of synapses. Despite their rapidly increasing prevalence within the aged population, progress in understanding the etiology and pathogenesis of these diseases, and developing therapies for them, has been severely hampered by the lack of suitable animal models. Further, microvascular disease is a common finding in the aged brain and it may precede the development of dementia. The ApoE4 gene is a predisposing factor for various types of vascular pathology as well as an important risk factor for the development of sporadic AD. The autosomal dominant disorder CADASIL, which results from mutations in the Notch3 gene, is a brain microvascular disease causing stroke and dementia and is characterized by thickening of the smooth muscle layer of brain arterioles. Agrin, a synapse organizing molecule in the peripheral nervous system, is expressed in normal brain but its function there remains unknown. In the central nervous system, it is found in neurons as well as within the basement membranes of the capillaries that form the blood brain barrier. Recent studies from two members of the project (Fallon and Stopa) have shown agrin redistributes to the Abeta-containing senile plagues and becomes insoluble in AD brains. These patients also exhibit fragmentation on the agrin-containment basement membranes of the brain microvasculature. In this proposal we will use tissue-specific targeted disruption of the agrin gene as a tool to study agrin function at synapses in normal brain (Aim #1) and in mouse models of AD (Aim #2). We will also examine the status of the microvasculature in mouse models of AD as well as in ApoE4 homozygous animals, particularly with respect to agrin expression in the basement membrane. Finally, we will generate mouse models of CADASIL (Aim #3) by 'knocking-in' mutant Notch3 alleles. We will characterize the microvasculature in these animals for comparison with CADASIL patients. We will also determine the prevalence of dominant Notch3 mutations in patients demonstrating MRI evidence of the CADASIL phenotype.