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Amyloid Beta Postsynaptic Signaling through AKAP-anchored Calcineurin

通过 AKAP 锚定的钙调神经磷酸酶进行淀粉样蛋白突触后信号传导

基本信息

批准号：
9269635
负责人：
MARK L DELL'ACQUA
金额：
$ 19.44万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269635
关键词：
A kinase anchoring protein Adult Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Brain Calcineurin Calcineurin inhibitor Calmodulin Cell Nucleus Chromosomes, Human, Pair 21 Chronic Conflict (Psychology)Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dementia Dendritic Spines Development Diagnostic Docking Down Syndrome Drug Targeting Equilibrium Excision Excitatory Synapse Functional disorder Future Gene Expression Gene Proteins General Population Genes Genetic Transcription Genetically Engineered Mouse Glutamate Receptor Hippocampus (Brain)Human Human Chromosomes Impaired cognition Impairment Individual Inherited Intellectual functioning disability Knock-in Mouse Laboratories Learning Light Link Long-Term Depression Long-Term Potentiation Mediating Memory Memory impairment Molecular Mus N-Methylaspartate Nerve Degeneration Neuronal Dysfunction Neuronal Plasticity Neurons Nuclear Translocation PPP3CA gene Pathology Pathway interactions Pharmacotherapy Phenotype Phosphorylation Phosphotransferases Presenile Alzheimer Dementia Protein Dephosphorylation Protein Fragment Proteins Publishing Receptor Activation Regulation Reporting Research Rodent Rodent Model Role Scaffolding Protein Senile Plaques Signal Pathway Signal Transduction Study models Synapses Synaptic Receptors Synaptic plasticity Testing Transcriptional Activation Vertebral column calcineurin phosphatase cognitive function early onset innovation interest mouse model new therapeutic target novel novel diagnostics nuclear factors of activated T-cells overexpression postsynaptic prevent receptor response synaptic depression synaptic function tau aggregation trafficking transcription factor voltage

项目摘要

Project Summary Abstract Amyloid Beta Postsynaptic Signaling through AKAP-anchored Calcineurin A overproduction from APP is believed to contribute to impaired synaptic plasticity and decreased cognitive function in Alzheimer’s disease (AD). Individuals with Down syndrome (DS; trisomy 21) have an extra copy of APP that predisposes them to early-onset AD. Thus, elucidating how A inhibits plasticity is important for understanding cognitive impairments associated with the development of dementia in AD and DS and could identify novel drug targets, diagnostics, and therapies. Rodent model studies indicate that calcineurin (CaN) phosphatase signaling could contribute to altered LTP/LTD synaptic plasticity, dendritic spine loss, and learning and memory impairments in AD. A-induced spine loss may be further linked to altered gene expression through CaN activation of the transcription factor NFAT. Here we propose to test the novel hypotheses that AKAP79/150-CaN anchoring is required for A activation of CaN signaling that regulates the balance between LTP/LTD signaling and NFAT transcription associated with dendritic spine/synapse loss.

项目摘要摘要 AKAP锚定的钙调神经磷酸酶介导的突触后信号转导 APP中的过度产生被认为是导致突触可塑性受损和减少的原因之一阿尔茨海默病(AD)的认知功能。唐氏综合征(DS；21三体)患者有一个额外的使他们易患早发性AD的APP副本。因此，阐明如何抑制可塑性是很重要的为了了解与AD和DS痴呆的发展相关的认知障碍，确定新的药物靶点、诊断和治疗方法。啮齿动物模型研究表明，钙调神经磷酸酶(CaN) 磷酸酶信号可能导致LTP/LTD突触可塑性改变，树突棘丢失，以及阿尔茨海默病的学习和记忆障碍。引起的脊椎缺失可能进一步与基因改变有关表达通过CaN激活转录因子NFAT。在这里，我们打算测试一下这部小说假设激活CAN信号需要AKAP79/150-CAN锚定，从而调节 LTP/LTD信号和NFAT转录之间的平衡与树突棘/突触丢失相关。