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Role of cofilin pathology in mouse models of cognitive impairment

丝切蛋白病理学在小鼠认知障碍模型中的作用

基本信息

批准号：
8664331
负责人：
JAMES R BAMBURG
金额：
$ 18.59万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664331
关键词：
Actins Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Appearance Atrophic Axon Behavior Behavioral Assay Binding Biological Assay Brain Brain region Bundling Cells Characteristics Cognitive Cognitive deficits Data Dementia Dendrites Development Distal Eukaryotic Cell Family Functional disorder Future Gene Activation Genes Glutamates Human Impaired cognition In Vitro Knock-in Mouse Knockout Mice Learning Link Mediating Membrane Memory Microfilaments Mitochondria Modeling Mus Mutant Strains Mice Mutate Mutation Myosin Type II NADPH Oxidase Neurites Neurons Neuropil Threads Nutraceutical Organism Oxidative Stress Pathology Pathway interactions Presenile Alzheimer Dementia Prions Production Protein Dephosphorylation Proteins Reactive Oxygen Species Resistance Role Senile Plaques Severities Shapes Slice Staging Stress Surface Synapses TNF gene Tamoxifen Testing Therapeutic Transgenic Mice Triterpenes actin depolymerizing factor amyloid peptide cell behavior cofilin cytokine dimer disulfide bond familial Alzheimer disease high reward high risk human subject in vivo inhibitor/antagonist member mild cognitive impairment mouse model mutant neuron loss overexpression oxidation presenilin prevent promoter public health relevance recombinase research study retinal rods scaffold stressor tau Proteins ursolic acid

项目摘要

DESCRIPTION (provided by applicant): Cofilin is a well-documented promoter of actin turnover in all eukaryotic cells. It undergoes dephosphorylation (activation) and oxidation to dimers when neurons are stressed by agents associated with Alzheimer disease (AD), all of which increase reactive oxygen species (ROS). This cofilin oxidation results within neurites in the formation of rod shaped cofilin-saturated actin bundles (rods). Rods immediately after their appearance are energy conserving, but when sustained causes neurite degeneration by blocking transport. Agents can induce rods via mitochondrial inhibition that generates ROS (e.g., excitotoxic glutamate) or via a prion-dependent pathway, probably involving membrane NADPH oxidase (NOX) activation. The latter pathway is activated by the proinflammatory cytokine TNF¿ as well as by soluble SDS-stable dimers/trimers of Amyloid-¿ (A¿d/t), the A¿ form that correlates best with dementia severity. Cofilin-actin rod formation causes the synapse elimination without neuronal cell death that is characteristic of amnestic mild cognitive impairment, an early stage in progression to Alzheimer disease. Our hypothesis is that it is cofilin-actin rods that initiate and exacerbate synaptic dysfunction typical of both sporadic (SAD) and familial AD (FAD). To demonstrate definitively that rod formation per se contributes to cognitive decline associated with AD, we need to develop a mouse model resistant to rod formation. Only a rod resistant mouse will allow us to answer the critical question: Do rods, themselves, cause synaptic loss or is synaptic loss due to stress-induced changes other than rod formation? It should be possible to make such a model since we have characterized a non-rod forming mutant of cofilin (K22Q), which is able to rescue normal behavior of cofilin-silenced cells as well as wild type cofilin. Three strategies are described to make a knock-in mouse in which cofilin K22Q will replace wild type cofilin. Two of these will make a conditional mouse which expresses wild type cofilin until mice are given tamoxifen. In these mice tamoxifen activates expression of Cre recombinase, which will initiate the inactivation of the wild type gene and the activation of the K22Q cofilin gene. The project is high risk since obtaining such a mouse is not guaranteed. Ultimately these mice will be used in behavioral assays to assess their cognitive ability under normal and stress conditions mimicking SAD or FAD. Finding that rods per se are necessary for synapse loss and cognitive impairment would make this project high reward because we already have identified a nutraceutical, the pentacyclic triterpene ursolic acid (UA), that blocks and reverses A¿d/t- and TNF¿-induced rods in cultured neurons and reverses oxidative stress markers and cognitive deficits in a brain oxidative stress mouse model. Thus we will determine if UA functions by reducing cofilin pathology and if it can be a major therapy for reducing cognitive deficits in mouse models of both SAD and FAD.

描述（由申请人提供）：Cofilin是所有真核细胞中肌动蛋白转换的良好记录的启动子。当神经元受到与阿尔茨海默病（AD）相关的药物的应激时，它经历去磷酸化（激活）和氧化成二聚体，所有这些都增加了活性氧（ROS）。这种cofilin氧化导致在神经突内形成棒状cofilin饱和的肌动蛋白束（棒）。杆状体在出现后立即保存能量，但如果持续存在，则会通过阻断运输导致神经突变性。药物可以通过产生ROS的线粒体抑制（例如，兴奋毒性谷氨酸）或通过朊病毒依赖途径诱导杆状细胞，可能涉及膜NADPH氧化酶（NOX）激活。后一种途径由促炎细胞因子TNF -以及可溶性的sds稳定的淀粉样蛋白二聚体/三聚体（A - d/t）激活，A - d/t与痴呆严重程度相关最好。Cofilin-actin棒的形成导致突触消除而没有神经元细胞死亡，这是遗忘性轻度认知障碍的特征，是阿尔茨海默病进展的早期阶段。我们的假设是，是cofilin-actin棒启动并加剧了散发性（SAD）典型的突触功能障碍。