Assessing effects of manipulation of expression of kinesins in a mouse modelof Alzheimer's disease

项目摘要 脑内异常蛋白质丝状沉积物的形成所引起的明显病变的存在， 神经元损伤是阿尔茨海默病（AD）的标志。这些丝状沉积物含有tau，一种突出的 通常稳定微管的细胞内蛋白质。纤维状β淀粉样蛋白斑块， 淀粉样前体蛋白（APP）的聚集是AD的另一个标志。多项研究表明， tau和APP是神经元中快速轴突运输的关键促进剂。重要的是，轴突运输涉及 几种神经精神疾病尽管轴突运输在AD中的因果作用尚不清楚，但一些研究表明， 已经报道了AD的tau和APP突变模型中的轴突运输缺陷。根据我们对 RNAi介导的功能丧失导致记忆丧失的驱动蛋白操纵的效果， 过度表达介导的功能获得导致记忆增强，我们在这里建议评估这种作用。 在AD的APP-NL-G-F敲入小鼠模型中驱动蛋白的过表达。具体来说，我们将研究 在改善斑块形成、小胶质细胞增生、突触蛋白和记忆缺陷中的过度表达。基于 在我们的研究中，我们证明了驱动蛋白过表达对记忆的增强作用，我们预计将观察到 APP NL-G-F敲入小鼠中细胞病理学和记忆缺陷的改善。积极成果， 这些研究预计将影响我们对AD病理生物学的理解，并发现新的治疗方法。 目标的

PROJECT SUMMARY The presence of distinct lesions caused by the formation of filamentous deposits of abnormal brain proteins in neurons is a hallmark of Alzheimer’s Disease (AD). These filamentous deposits contain tau, a prominent intracellular protein that normally stabilizes microtubules. Fibrillar amyloid beta plaques arising from the aggregation of amyloid precursor protein (APP) is another hallmark of AD. Several studies have shown that both tau and APP are key facilitators of fast axonal transport in neurons. Importantly, axonal transport is implicated in several neuropsychiatric disorders. Though a causal role of axonal transport in AD is not known, several studies have reported axonal transport deficits both in tau and APP mutant models of AD. Based on our studies on the effect of manipulation of kinesins that RNAi mediated loss of function resulting in loss of memory whereas overexpression mediated gain of function resulting in enhanced memory, we here propose to assess the effect of overexpression of kinesins in APP-NL-G-F knockin mouse model of AD. Specifically we will study the effect of overexpression in ameliorating plaque formation, microgliosis, synaptic proteins and memory deficit. Based on our studies demonstrating memory enhancement with Kinesin overexpression, we anticipate to observe improvements in cytopathology and memory deficit in APP NL-G-F knockin mice. Positive outcomes from these studies are expected to impact our understanding of pathobiology of AD and discovery of new therapeutic targets.