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（由适用提供）：Cofilin是所有真核细胞中肌动蛋白更新的启动子。当神经元与阿尔茨海默氏病（AD）强调神经元时，它经历了去磷酸化（激活）和氧化对二聚体的氧化，所有这些都会增加活性氧（ROS）。这种cofilin氧化在神经运动中导致杆状cofilin饱和肌动蛋白束（杆）的形成。后一种途径后立即通过促炎性细胞因子TNF以及淀粉样蛋白 - 淀粉样蛋白的固体SDS稳定二聚体/三聚体（a¿d/t）激活后，这是与痴呆症的严重程度最大的相关性。 Cofilin-actin杆的形成会导致突触消除，而没有神经元细胞死亡，这是淡淡的轻度认知障碍的特征，这是阿尔茨海默氏病发展的早期阶段。我们的假设是，既有偶然的cofilin-actin棒启动和加剧了突触的功能障碍和家庭广告（时尚）。为了确定证明杆的形成本身有助于与AD相关的认知下降，我们需要开发一种抗杆形成的小鼠模型。只有耐棒小鼠才能使我们回答一个关键的问题：杆本身会导致合成损失，还是由于压力形成以外的压力诱导的变化而导致的合成损失？由于我们已经表征了Cofilin（K22Q）的非螺旋形成突变体，因此应该可以制作这种模型，该突变体能够挽救Cofilin脱毛细胞以及野生型Cofilin的正常行为。描述了三种策略，以制造出cofilin k22q将取代野生型cofilin的敲击小鼠。其中两个将制作有条件的小鼠，该小鼠表达野生型Cofilin，直到给小鼠他莫昔芬为止。在这些小鼠中以及K22Q Cofilin基因的激活。该项目是高风险，因为不能保证获得这种鼠标。最终，这些小鼠将在行为评估中使用，以评估其在正常情况下的认知能力，并模仿SAD或FAD的压力条件。 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 reverse oxidative stress markers and cognitive deficiencies in a brain oxidative stress mouse model.我们将确定UA是否通过减少Cofilin病理学以及可以减少SAD和FAD小鼠模型中认知缺陷的主要疗法来确定UA的功能。