The Role of MICU3 in Alzheimer's Disease Pathogenesis

MICU3 在阿尔茨海默病发病机制中的作用

基本信息

批准号：
10677454
负责人：
Henry Cohen
金额：
$ 3.34万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677454
关键词：
1 year old 3xTg-AD mouse Ablation Address Affect Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid Amyloid beta-Protein Aphasia Biological Assay Biological Availability Brain Calcium Cell Death Cell Line Central Nervous System Clinical Clinical Trials Cognitive deficits Conceptions Coupled Cues Data Deposition Development Disease Enterobacteria phage P1 Cre recombinase Failure Genes Genetic Genetic Predisposition to Disease Glycolysis Hippocampus Histopathology Homeostasis Human Impaired cognition In Vitro Intervention Knock-out Knockout Mice Learning Measures Mediating Membrane Membrane Potentials Memory Metabolic Mitochondria Mitochondrial Swelling Modeling Molecular Motor Motor Activity Mus Mutant Strains Mice Nerve Degeneration Neurocognitive Neurocognitive Deficit Neuronal Dysfunction Neurons Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Phenotype Physiology Probability Production Prosencephalon Protein Family Reactive Oxygen Species Regulation Reporter Reporting Respiration Role Rotarod Performance Test Rupture Sampling Series Stress Superoxides Tamoxifen Testing Therapeutic Time aged brain parenchyma calcium uniporter conditioned fear constitutive expression extracellular follow-up human old age (65+)inducible Cre mitochondrial membrane mitochondrial metabolism mouse model mutant neuromuscular neuron loss overexpression ratiometric response targeted treatment tau Proteins therapeutic target therapeutically effective uptake

1 year old 3xTg-AD mouse Ablation Address Affect Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid Amyloid beta-Protein Aphasia Biological Assay Biological Availability Brain Calcium Cell Death Cell Line Central Nervous System Clinical Clinical Trials Cognitive deficits Conceptions Coupled Cues Data Deposition Development Disease Enterobacteria phage P1 Cre recombinase Failure Genes Genetic Genetic Predisposition to Disease Glycolysis Hippocampus Histopathology Homeostasis Human Impaired cognition In Vitro Intervention Knock-out Knockout Mice Learning Measures Mediating Membrane Membrane Potentials Memory Metabolic Mitochondria Mitochondrial Swelling Modeling Molecular Motor Motor Activity Mus Mutant Strains Mice Nerve Degeneration Neurocognitive Neurocognitive Deficit Neuronal Dysfunction Neurons Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Phenotype Physiology Probability Production Prosencephalon Protein Family Reactive Oxygen Species Regulation Reporter Reporting Respiration Role Rotarod Performance Test Rupture Sampling Series Stress Superoxides Tamoxifen Testing Therapeutic Time aged brain parenchyma calcium uniporter conditioned fear constitutive expression extracellular follow-up human old age (65+)inducible Cre mitochondrial membrane mitochondrial metabolism mouse model mutant neuromuscular neuron loss overexpression ratiometric response targeted treatment tau Proteins therapeutic target therapeutically effective uptake

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项目摘要

PROJECT ABSTRACT 6.2M Americans over the age of 65 suffer from Alzheimer’s disease (AD) and this number expected to double in ~30 years. AD is characterized by aphasia, loss of fine and gross motor function, and rapid cognitive decline. The widely favored “amyloid hypothesis” of AD posits that accumulation of fibrillar amyloid beta (Aβ) plaques in the brain parenchyma drives AD pathogenesis. However, the amyloid pathway has proven to be an ineffective therapeutic target in numerous clinical trials and AD remains clinically intractable, highlighting the urgent need for deeper understanding of the underlying mechanisms of disease. Our lab previously reported that mitochondrial calcium (mCa2+) overload promotes AD pathogenesis. mCa2+ homeostasis is maintained through regulation of mCa2+ uptake through the mitochondrial calcium uniporter channel (mtCU) and mCa2+ efflux through the mitochondrial Na+/Ca2+ exchanger (NCLX). Human cortex from sporadic AD patients demonstrates >70% reduction in NCLX expression. Genetic rescue of mCa2+ efflux via hippocampal neuron-specific expression of NCLX protects against mCa2+ overload, ROS-stress, Aβ and tau deposition, and cognitive decline in AD mutant mice. We interpret remodeling of mCa2+ transport as a compensatory response to an early pathologic stress (e.g., energetic crisis, aging, genetic predisposition) to increase ATP bioavailability. Over time, this response turns maladaptive and promotes pathologic mCa2+ overload. mCa2+ overload causes excessive production of reactive oxygen species (ROS), metabolic derangement, and cell death, all hallmarks of AD. Although a robust connection between neuronal mCa2+ overload and AD pathogenesis has been established, how altered regulation of mCa2+ uptake promotes or protects against AD pathology remains completely unexplored. Our preliminary data demonstrates MICU3 expression is significantly reduced by ~50% in multiple cortical regions of samples isolated from sporadic AD patients. Further, MICU3 expression is reduced >90% in the cortex of 1 year-old. 3xTg-AD mutant mice. This proposal hypothesizes that loss of neuronal Micu3 contributes to aberrant mtCU-mediated mCa2+ uptake, resulting in mCa2+ overload, metabolic derangement, neuronal dysfunction, and cognitive decline in AD. To address this hypothesis we will utilize newly generated neuron-specific MICU3 knockout mouse lines to measure if knockout of MICU3 alone is sufficient to cause neurodegeneration. Subsequently, we will use our newly developed cre-inducible MICU3 overexpression mouse line to see if rescuing MICU3 levels shortly after onset of cognitive decline in the APPNL-G-F mouse model of AD is sufficient to mitigate or reverse AD pathology. These studies will be followed up with a series of mechanistic in vitro studies to determine the molecular mechanism of MICU3-mediated neuronal dysfunction in AD. The role of MICU3 in physiology and disease states, including AD, is unknown; coupled with our findings that altered mCa2+ handling is a pathologic feature of and promising therapeutic target for AD provides strong rationale for this proposal.

项目摘要 65岁以上的620万美国人患有阿尔茨海默氏病（AD），这一数字预计将两倍〜30年。 AD的特征是失语症，罚款和总体运动功能的丧失以及快速认知能力下降。广泛优选的AD正电子的“淀粉样假说”，即纤维淀粉样β（Aβ）斑块的积累大脑实质驱动AD发病机理。但是，淀粉样蛋白途径已被证明是无效的在众多临床试验和AD中，治疗靶标保持临床上的棘手，强调了迫切需求为了深入了解疾病的潜在机制。我们的实验室以前报告说线粒体钙（MCA2+）过载促进了AD发病机理。 MCA2+稳态通过通过线粒体钙Uniter通道（MTCU）和MCA2+外排调节MCA2+摄取线粒体Na+/Ca2+交换器（NCLX）。来自零星AD患者的人皮质表现> 70％ NCLX表达的降低。通过海马神经特异性表达MCA2+外排的遗传营救 NCLX可预防MCA2+过载，ROS肌，Aβ和TAU沉积以及AD突变体的认知下降老鼠。我们将MCA2+转运的重塑解释为对早期病理应激的补偿性反应（例如，充满活力的危机，衰老，遗传倾向），以增加ATP生物利用度。随着时间的流逝，这种响应转弯适应不良并促进病理MCA2+超负荷。 MCA2+超负荷导致反应性过多氧（ROS），代谢进化和细胞死亡，都是AD的所有标志。虽然很健壮神经元MCA2+超负荷和AD发病机理之间的联系如何改变调节 MCA2+摄取的促进或预防AD病理仍然是完全出乎意料的。我们的初步数据表明，在多个皮质区域，MICU3表达显着降低了约50％从零星的AD患者中分离出来。此外，在1岁的皮层中，MICU3表达降低了> 90％。 3XTG-AD突变小鼠。该提议假设神经元MICU3的丧失导致异常 MTCU介导的MCA2+摄取，导致MCA2+过载，代谢进化，神经元功能障碍，和AD认知能力下降。为了解决这一假设，我们将利用新生成的神经特异性MICU3 敲除小鼠线以测量单独的MICU3敲除足以引起神经变性。随后，我们将使用新开发的CRE诱导MICU3过表达鼠标线，以查看是否是否 APPNL-G-F小鼠模型的认知下降开始后不久，拯救MICU3水平就足够了减轻或逆转AD病理学。这些研究将进行一系列机械性研究确定AD中MICU3介导的神经元功能障碍的分子机制。 Micu3在包括AD在内的生理学和疾病状态尚不清楚。再加上我们改变MCA2+处理的发现是AD的病理特征和承诺的治疗靶标的该提案提供了强有力的理由。