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

评估阿尔茨海默病小鼠模型中驱动蛋白表达的操纵效果

基本信息

批准号：
10447995
负责人：
Sathyanarayanan V Puthanveettil
金额：
$ 38.64万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447995
关键词：
Address Afferent Neurons Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Aplysia Area Axonal Transport Basic Science Behavior Biology Cells Characteristics Cognitive deficits Cytopathology Defect Dementia Deposition Development Frontotemporal Dementia Funding Opportunities Genetic Transcription Gills Gliosis Green Fluorescent Proteins Image Injections Kinesin Knock-in Knock-in Mouse Knowledge Laboratories Lesion MAPT gene Mediating Memory Memory Loss Memory impairment Microtubule Stabilization Microtubules Modeling Molecular Motors Motor Motor Neurons Mus Mutation Neurodegenerative Disorders Neurons Organelles Outcome Outcome Study Parkinson Disease Prosencephalon Protein Family Protein Overexpression Proteins Publishing RNA RNA Interference Reflex action Reporting Research Research Personnel Research Project Grants Role Senile Plaques Short-Term Memory Swedish mutation Symptoms Synapses Synaptic plasticity Tauopathies Testing Withdrawal base brain abnormalities cognitive enhancement experimental study fast axonal transport gain of function gene product improved insight interest long term memory loss of function member mouse model mutant neonatal mice neuropsychiatric disorder new therapeutic target next generation novel therapeutics overexpression particle programs response sea slug spatial memory synaptic function synaptogenesis tau Proteins tau aggregation

项目摘要

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.

项目概要由异常脑蛋白丝状沉积物的形成引起的明显病变的存在神经元是阿尔茨海默病 (AD) 的一个标志，这些丝状沉积物含有 tau 蛋白，这是一种重要的物质。通常稳定微管产生的纤维状淀粉样蛋白斑块的细胞内蛋白。淀粉样前体蛋白 (APP) 的聚集是 AD 的另一个标志。 tau 和 APP 是神经元快速轴突运输的关键促进者，重要的是，轴突运输参与其中。尽管轴突运输在 AD 中的因果作用尚不清楚，但有几项研究表明。根据我们对 AD 的研究，报道了 tau 和 APP 突变模型中的轴突运输缺陷。 RNAi 介导的驱动蛋白操纵效应导致功能丧失，导致记忆丧失，而过度表达介导的功能增益导致记忆增强，我们在此建议评估其效果具体来说，我们将研究 APP-NL-G-F 敲入 AD 小鼠模型中驱动蛋白过度表达的影响。基于改善斑块形成、小胶质细胞增生、突触蛋白和记忆缺陷的过度表达。我们的研究表明驱动蛋白过度表达可增强记忆力，我们预计会观察到 APP NL-G-F 敲入小鼠的细胞病理学和记忆缺陷得到改善。研究预计将影响我们对 AD 病理学的理解和新疗法的发现目标。