ADF/cofilin-actin rods in neurodegenerative diseases

ADF/丝切蛋白-肌动蛋白棒在神经退行性疾病中的作用

基本信息

批准号：
7591023
负责人：
JAMES R BAMBURG
金额：
$ 32.12万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-12-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591023
关键词：
ATP Hydrolysis Actins Affect Affinity Aftercare Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Apoptosis Binding Brain Brain Diseases Brain region Cell Culture Techniques Cells Cerebellum Cleaved cell Culture Media Deposition Disease Disease Progression Distal Dose Endocytosis Glutamates Grant Growth Hippocampus (Brain)Human Injury Intervention Ischemia Lead Mediating Membrane Lipids Mitochondria Modeling Molecular Conformation Mus Mutation Nature Nerve Growth Factor Receptors Neurites Neurodegenerative Disorders Neurons Neuropil Niemann-Pick Diseases Pathway interactions Peptides Peroxides Pertussis Toxin Process Production Property Proteins Public Health Quality of life Rattus Role Senile Plaques Shapes Side Site Slice Small Interfering RNA Stress Structure Surface Synapses Testing Tg2576 Transgenic Mice Transport Vesicles Vesicle Western Blotting beta secretase cofilin conformer immunoreactivity mutant prevent protein aggregate response retinal rods secretase transcriptional coactivator p75

项目摘要

Within neurites of nearly all cultured hippocampal neurons, transient ATP depletion rapidly inducesrod- shaped structures composed primarily of actin and ADF/cofilin (AC). Rod formation, which sequesters a portion of the actin but virtually all of the AC, is transiently beneficial to the stressed neuron because it spares ATP associated with actin turnover. However, rods can completely occlude the neurite, blocking transport and causing distal neurite withering. Rods are prominent features of Alzeimer's disease (AD) brain but not of control human brain lacking amyloid plaques. Similar structures are found in brains of animals with Niemann-Pick disease typed (NPC1) and of transgenic mice (Tg2576) expressing mutant human amyloid precursor protein (APP). In cultured neurons and mouse brain slices, rods are induced by ischemia, peroxide, NO, and excitotoxic glutamate. In up to 20% of hippocampal neurons, whether from region CA1 or CAS, the AD amyloid beta peptide (Ab) also induces rods: induction is dose-dependent, occuring within 6 h after treatment and plateauing 12-24 h later. As little as 10 nM of Ab oligomer has a significant effect compared to the scrambled peptide control. The nature of the sensitivity of only a subset of neurons to Ab will be explored. Rods block vesicular transport of APP. APP-containing vesicles accumulate at the ends and sides of rods. Within these stalled vesicles is beta-secretase cleaved APP, suggesting that these may be sites of Ab production and/or conversion into more damaging conformers. Taken together, these results suggest a model for AD in which neuronal stress, including Ab formed in familial AD, induces rods that stall vesicle transport and increase toxic Ab, thus inducing rods in neighboring cells. Such a model could explain the formation of amyloid plaques, which would enlarge around the initial site of injury. Using cell culture and organotypic brain slices, we will determine: 1) what activities of cofilin are required for rod formation; 2) if mutations in AC can be identified that prevent rod formation; 3) if rods promote the production or oligomerization of Ab; 4) what makes a subset of neurons sensitive to Ab: and 5) how organotypic brain slices can be used as a model to study where rods form and how they disrupt synapses. Relevance to public health: AD dramatically impacts life quality of senior Americans, affecting 25% of those > 85. This proposal tests a new hypothesis for AD progression and identifies possible sites for targeted intervention.

在几乎所有培养的海马神经元的神经突中，瞬态ATP耗竭迅速诱导形状结构主要由肌动蛋白和ADF/Cofilin（AC）组成。杆形成，隔离肌动蛋白的一部分，但实际上全部AC，对压力神经元瞬时有益，因为它备件与肌动蛋白周转相关。但是，杆可以完全阻塞神经突，阻塞运输并导致远端神经突。杆是Alzeimer病（AD）大脑的突出特征但不能控制缺乏淀粉样斑块的人脑。在动物的大脑中发现了类似的结构与尼曼 - 踢疾病分型（NPC1）和转基因小鼠（TG2576）表达突变的人（TG2576）淀粉样前体蛋白（APP）。在培养的神经元和小鼠脑切片中，杆子是由缺血诱导的，过氧化物，NO和兴奋性谷氨酸。多达20％的海马神经元，无论是来自CA1还是来自区域 CAS，AD淀粉样蛋白β肽（AB）也诱导杆：诱导是剂量依赖性的，发生在6小时之内治疗后12-24小时后平稳。仅10 nm的AB低聚物具有显着效果与炒肽对照相比。仅神经元对AB的敏感性的性质将被探索。杆阻止应用程序的囊泡运输。含有应用的囊泡在末端积聚和杆的侧面。在这些停滞的囊泡中，是β-分泌酶切割应用程序，这表明这些可能成为AB生产和/或转换为更具破坏性构象体的站点。总之，这些结果提出一个模型的AD模型，其中神经元应力（包括在家族性AD中形成的AB）诱导停滞的棒囊泡转运并增加有毒的AB，从而诱导邻近细胞中的棒。这样的模型可以解释淀粉样斑块的形成将在最初的受伤部位扩大。使用细胞培养和器官型脑切片，我们将确定：1）杆形成需要哪些Cofilin的活性； 2）如果可以鉴定出AC中的突变，以防止杆形成； 3）如果杆促进生产或 AB的寡聚； 4）是什么使神经元的子集对AB敏感：5）器官型大脑如何切片可以用作研究杆形成的位置以及如何破坏突触的模型。与公共卫生：广告极大地影响美国人的生活质量，影响其中25％> 85。建议检验一个新的假设，用于AD进展，并确定有针对性干预的可能地点。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Growth cone-like waves transport actin and promote axonogenesis and neurite branching.

DOI：
10.1002/dneu.20734
发表时间：
2009-10
期刊：
DEVELOPMENTAL NEUROBIOLOGY
影响因子：
3
作者：
Flynn, Kevin C.;Pak, Chi W.;Shaw, Alisa E.;Bradke, Frank;Bamburg, James R.
通讯作者：
Bamburg, James R.

Production and use of replication-deficient adenovirus for transgene expression in neurons.

复制缺陷型腺病毒的生产和使用用于神经元转基因表达。

DOI：
10.1016/s0091-679x(03)01019-7
发表时间：
2003
期刊：
Methods in cell biology
影响因子：
0
作者：
Minamide,LS;Shaw,AE;Sarmiere,PD;Wiggan,O;Maloney,MT;Bernstein,BarbaraW;Sneider,JM;Gonzalez,JA;Bamburg,JamesR
通讯作者：
Bamburg,JamesR

Introduction to cytoskeletal dynamics and pathfinding of neuronal growth cones.

细胞骨架动力学简介和神经元生长锥寻路。