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Calcineurin activation and scaffolding in A Beta-induced synaptic dysfunction

A Beta 诱导的突触功能障碍中钙调神经磷酸酶的激活和支架

基本信息

批准号：
10668499
负责人：
Olga Prikhodko
金额：
$ 7.38万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2024-08-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10668499
关键词：
A kinase anchoring protein Acute Address Affect Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Architecture Behavioral Binding Binding Sites Biological Assay Calcineurin Calcineurin inhibitor Cell membrane Chronic Complex Data Dementia Dendritic Spines Disease Docking Endocytosis Excision Excitatory Synapse Exhibits Exocytosis Exposure to Functional disorder Future Genetically Engineered Mouse Glutamate Receptor Hippocampus Immunosuppression Impaired cognition Impairment In Vitro Kidney Knock-in Mouse Lead Learning Long-Term Depression Long-Term Potentiation Measures Mediating Memory Memory impairment Molecular Mus Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Nervous System Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Plasticity Neurons Organ Pathologic Pathology Pathway interactions Peptides Persons Phosphorylation Postsynaptic Membrane Prevalence Prevention Probability Protein Dephosphorylation Protein phosphatase Proteins Radial Regulation Reporting Research Resistance Rodent Model Scaffolding Protein Senile Plaques Signal Pathway Signal Transduction Site Specificity Stimulus Synapses Synaptic plasticity Testing Toxic effect Wild Type Mouse Work aging population arm behavioral impairment calcineurin phosphatase conditioned fear cost effective therapy familial Alzheimer disease hippocampal pyramidal neuron in vivo long term memory mouse model mutant neurotransmission new therapeutic target novel novel therapeutic intervention pharmacologic postsynaptic prevent protective effect receptor receptor function scaffold small molecule inhibitor symptom treatment synaptic function tau Proteins therapeutic target water maze

项目摘要

Project Summary Alzheimer’s disease (AD) is the most common form of dementia, with growing prevalence as the aging population continues to grow. Pathologically, this neurodegenerative disease is characterized by amyloid-β (Aβ) plaques and tau tangles. Acute application of Aβ has been shown to inhibit NMDA receptor (NMDAR)- dependent long-term potentiation (LTP, a key form of neuronal plasticity critical for learning and memory), and chronic Aβ exposure caused long-term depression (LTD) and elimination of excitatory synapses. Normal LTD requires the protein phosphatase Calcineurin (CaN) and pharmacological inhibition of CaN prevents Aβ- mediated LTP inhibition and synapse loss in rodent models. However, we not know where in the complex organization and architecture of the nervous system CaN is acting to promote these deleterious impacts of Ab on synaptic function. Here I will test the novel hypothesis that LTP inhibition, excitiatory synapse loss, and impaired cognition associated with mouse models of AD are due to Aβ triggering aberrant postsynaptic CaN activation in hippocampal pyramidal neurons. I will further test whether CaN that is specifically localized to postsynaptic sites by the scaffolding protein AKAP79/150 is responsible for mediating these synaptotoxic effects of Aβ at the molecular, cellular and behavioral levels in an effort to uncover potentially new therapeutic targets.

项目摘要阿尔茨海默病(AD)是最常见的痴呆症，随着年龄的增长，其患病率不断上升人口继续增长。病理上，这种神经退行性疾病的特征是淀粉样蛋白-β (Aβ)斑块和牛磺酸缠结。β的急性应用被证明能抑制NMDAR- 依赖长时程增强(LTP，一种对学习和记忆至关重要的神经元可塑性的关键形式)，以及慢性A-β暴露导致长期抑郁(LTD)和兴奋性突触的消除。Normal Ltd 需要蛋白磷酸酶钙调神经磷酸酶(CaN)和CaN的药物抑制来预防Aβ- 在啮齿动物模型中介导LTP抑制和突触丢失。然而，我们不知道在建筑群的什么地方神经系统的组织和结构正在促进抗体的这些有害影响关于突触功能。在这里，我将测试LTP抑制、兴奋性突触丢失和阿尔茨海默病小鼠模型相关的认知障碍是由于β触发异常的突触后CAN 海马区锥体神经元的激活。我将进一步测试是否可以将其具体定位到突触后部位由支架蛋白AKAP79/150负责介导这些突触毒性 β在分子、细胞和行为水平上的作用，以努力发现潜在的新疗法目标。