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.

项目摘要由于形成异常脑蛋白的丝状沉积物引起的不同病变的存在神经元是阿尔茨海默氏病（AD）的标志。这些丝状沉积物包含tau，一个突出的通常稳定微管的细胞内蛋白。原纤维淀粉样β斑块是由淀粉样蛋白前体蛋白（APP）的聚集是AD的另一个标志。几项研究表明，两者都 TAU和APP是神经元快速轴突运输的关键促进因子。重要的是，轴突运输是在几种神经精神疾病。尽管轴突运输在AD中的因果作用尚不清楚，但几项研究已经报道了轴突运输在AD的TAU和APP突变模型中都定义了。根据我们对 RNAi介导的功能丧失导致记忆力丧失的操纵的驱动蛋白的作用过表达介导的功能增益，导致记忆增强，我们在这里提出评估效果的建议 App-nl-g-f敲击蛋白小鼠模型中驱动蛋白的过表达。具体而言，我们将研究效果改善斑块形成，小胶质细胞增多，突触蛋白和记忆防御的过表达。基于在我们的研究中证明了通过驱动蛋白过表达增强记忆力的研究，我们预计会观察到 APP NL-G-F敲门蛋白小鼠的细胞病理学和记忆缺陷的改善。这些积极的结果期望研究会影响我们对AD病理生物学的理解和新疗法的发现目标。