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

项目总结 脑部异常蛋白形成丝状沉积引起的明显损害 神经元是阿尔茨海默病(AD)的标志。这些丝状沉积物中含有一种重要的 正常情况下稳定微管的细胞内蛋白质。纤维样β淀粉样斑块起源于 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，两者都 Tau和APP是神经元快速轴突运输的关键促进器。重要的是，轴突运输与 几种神经精神障碍。尽管轴突运输在阿尔茨海默病中的因果作用尚不清楚，但几项研究 已经报道了在tau和app突变的AD模型中轴突运输缺陷。基于我们对 RNAi介导的功能丧失导致记忆丧失的运动蛋白操纵效应 过度表达介导的功能获得导致记忆增强，我们建议评估其效果 APP-NL-G-F敲门小鼠AD模型中Kinesin的过度表达。具体地说，我们将研究其影响 在改善斑块形成、小胶质细胞增多症、突触蛋白和记忆障碍方面的过度表达。基座 在我们的研究中，我们预计会观察到Kinesin的过度表达会增强记忆 APP NL-G-F敲击小鼠细胞病理学和记忆缺陷的改善。这些都带来了积极的结果 研究有望影响我们对阿尔茨海默病病理生物学的理解和发现新的治疗方法 目标。

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.