Regulation of Neuronal Clearance Pathways via Nuclear Calcium Signaling in Alzheimer's Disease

阿尔茨海默病中通过核钙信号传导调节神经元清除途径

基本信息

批准号：
10414075
负责人：
WILMA J FRIEDMAN
金额：
$ 45.19万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414075
关键词：
ATF6 gene Abeta clearance Adult Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Attenuated Automobile Driving Autopsy Axon Biological Models Brain Calcium Calcium Signaling Cells Characteristics Cyclic AMP-Responsive DNA-Binding Protein Data Deposition Development Disease Disease Progression Drosophila genus Drosophila melanogaster Early Onset Familial Alzheimer&apos s Disease Enzymes Etiology FOXO3A gene Failure Functional disorder Future Gene Expression Genes Goals Histone Acetylation Histones Homeostasis Human Human Amyloid Precursor Protein Human Genome Impairment Link Mediating Mediator of activation protein Molecular Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Onset of illness Pathogenesis Pathologic Pathway interactions Patients Peptide Hydrolases Pharmacology Physiological Play Prosencephalon Proteins Publishing Regulation Reporting Role Ryanodine Receptor Calcium Release Channel Senile Plaques Signal Transduction Site Stress Swelling System Tauopathies Testing Time Work aged amyloid precursor protein processing brain tissue effective therapy familial Alzheimer disease flexibility fly functional decline genetic manipulation in vivo induced pluripotent stem cell mouse model mutant neuron loss neuronal survival neuroprotection neurotoxic novel novel strategies overexpression presenilin prevent protein transport tau Proteins tau aggregation tau mutation therapy development trafficking transcription factor

项目摘要

Abstract Inhibition of the autolysosomal system has recently been described among the earliest changes in Alzheimer’s disease (AD) brains and likely contributes to the pathological hallmarks of AD: amyloid plaques and neurofibrillary Tau tangles that drive neurodegeneration. Impairment of the autolysosomal system and consequent disruption of molecular clearance are causally linked to increased neuronal vulnerability and neurodegeneration. Our recently published studies show that nuclear activity of the transcription factor EB (TFEB) and many cellular clearance mechanisms, are greatly attenuated in Presenilin (PS) deficiency, which is the leading cause for early onset familial AD (FAD). In our preliminary studies, we find that a decrease of nuclear calcium levels and consequently cAMP response element-binding protein (CREB)-mediated expression of its target genes associated with the autolysosomal pathway is the underlying mechanism for attenuated molecular clearance and decreased neuroprotection in PS and Tau mutants. Expression of the CREB-target gene sestrin 2 (sesn2) in human AD neurons promotes autophagic clearance and neuronal survival under stress conditions. We hypothesize that PS1 and Tau mutants impair Ryanodine Receptor (RyR)-mediated control of nuclear calcium, which promotes clearance of neurotoxic proteins that accumulate in the AD brain. If our hypothesis is correct, these studies will identify a novel pathway that drives formation of the pathological hallmarks associated with AD. Induced pluripotent stem cell (iPSC)-derived human forebrain neurons and Drosophila melanogaster will be used to assess the impact of nuclear calcium depletion and reduced pCREB signaling in molecular clearance during AD onset and progression. We seek to assess the relevance of our findings in postmortem human brain tissues from patients with early, mid and advanced AD. The use of complementary model systems allows us to assess causality: in human neurons that express physiological levels of disease-associated, aggregation-prone proteins, and in Drosophila melanogaster, a model organism with less complexity and redundancy than the human genome that can be genetically manipulated and physiologically aged. The overall goal of this proposal is 1) to understand the mechanisms leading to inhibition of molecular clearance in AD brains, and 2) to identify consequences of functional failure of neuronal clearance in aging and AD neurons to facilitate future development of interventions enhancing neuronal clearance and prevent neurodegeneration.

抽象的自体溶酶体系统的抑制最近被描述为阿尔茨海默病最早的变化之一疾病 (AD) 大脑，并可能导致 AD 的病理特征：淀粉样斑块和神经原纤维 Tau 缠结会导致自体溶酶体系统损伤和神经变性。随之而来的分子清除的破坏与神经脆弱性的增加有因果关系我们最近发表的研究表明转录因子 EB 的核活性。 (TFEB) 和许多细胞清除机制，在早老素 (PS) 缺乏时会大大减弱，这是在我们的初步研究中，我们发现核的减少是导致早发家族性 AD (FAD) 的主要原因。钙水平及其随后的 cAMP 反应元件结合蛋白 (CREB) 介导的表达与自溶酶体途径相关的靶基因是减弱分子作用的潜在机制 CREB 靶基因 sestrin 的清除和神经保护作用降低。人类 AD 神经元中的 2 (sesn2) 可促进应激条件下的自噬清除和神经元存活。我们追踪 PS1 和 Tau 突变体损害 Ryanodine 受体 (RyR) 介导的核控制如果我们的假设是的话，钙会促进 AD 大脑中积聚的神经毒性蛋白质的清除。正确的是，这些研究将确定一种新的途径来驱动相关病理特征的形成诱导多能干细胞 (iPSC) 衍生的人类前脑神经元和果蝇将用于评估核钙消耗和 pCREB 信号传导减少对分子的影响我们试图评估我们的尸检结果的相关性。来自早期、中期和晚期 AD 患者的人类脑组织的互补模型系统的使用。使我们能够评估因果关系：在表达疾病相关生理水平的人类神经元中，易于聚集的蛋白质，以及果蝇（一种复杂性较低的模式生物）比人类基因组更冗余，可以进行基因操纵和生理老化。该提案的目标是 1) 了解导致 AD 中分子清除受到抑制的机制 2) 识别衰老和 AD 神经元中神经元清除功能失败的后果促进未来增强神经清除和预防神经变性的干预措施的发展。