A multi-scale data-driven model of the Abeta pore function and Ca2+ toxicity in Alzheimer's disease

阿尔茨海默病中 Abeta 孔函数和 Ca2 毒性的多尺度数据驱动模型

基本信息

批准号：
9334044
负责人：
Angelo Demuro
金额：
$ 41.2万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2016-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334044
关键词：
Affect Aluminum Alzheimer&apos s Disease Amyloid beta-Protein Behavior Behavior monitoring Bexarotene Biological Cell Death Cell membrane Cell model Cells Cessation of life Cholesterol Chronic Complex Computer Simulation Computer software Copper Curcumin Custom Data Data Analyses Detection Deterioration Development Etiology Event Evolution Goals Hour Image Image Analysis Imaging Techniques Individual Intracellular Membranes Ion Channel Kinetics Lysosomes Measures Mediating Membrane Membrane Potentials Memory Loss Methodology Mitochondria Modeling Molecular Monitor Nature Neurodegenerative Disorders Neurons Optical Methods Optics Organelles Patch-Clamp Techniques Pathogenesis Pathogenicity Pathologic Pathology Peptides Permeability Pharmacology Phenols Phosphatidylserines Population Probability Procedures Property Research Resolution Resveratrol Side Signal Transduction Technology Testing Time Toxic effect Variant Xenopus oocyte Zinc abeta oligomer abeta toxicity base cell motility cognitive function computer framework experimental study extracellular imaging approach improved millisecond novel protein aggregate simulation small molecule therapeutic target tool

项目摘要

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that leads to progressive deterioration in a broad range of cognitive functions and finally death. Three amyloid beta (Aβ) peptides, Aβ40, Aβ42, and Aβ43 have been implicated as a key factors in the pathogenesis of AD. Recent findings indicate that extra- and intracellular accumulations of oligomeric forms of Aβ rather than large insoluble aggregates are the likely pathological culprits, and that their toxicity is mediated through uncontrolled elevation of cytosolic Ca2+ by formation of toxic Ca2+-permeable pores in the plasma membrane (PM). Yet, detailed information about the function of different Aβ pore types and which leaflet of the PM is more susceptible to pore formation are lacking. These pores have shown significant diversity and time dependent changes in their functional properties. Moreover, pharmacological comparisons between pores due to the three types of peptides are lacking. The highly heterogeneous and dynamic nature of Aβ pores poses extreme challenges in investigating their pathogenic mechanisms through traditional single channel approaches. Our goal is to fill a critical void in the understanding of Aβ-mediated Ca2+ signaling disruptions in AD using multi-scale data-driven modeling in conjunction with advanced imaging techniques having a resolution down to single channel level. Using our optical patch clamp technique, we will monitor and compare the gating properties and time- dependent evolution of hundreds of Aβ pores formed by extra- and intracellular Aβ oligomers. We will measure and compare the conductance properties, gating kinetics, and time-dependent evolution of the three Aβ pore types. We propose to perform parallel experiments on Aβ40, Aβ42, and Aβ43 pores in identical conditions to: (1) elucidate and compare their function in the presence of various modulators including Zinc, Aluminum, and Copper, (2) compare the effects of Aβ pore blockers such as NA7 and Bexarotene, (3) how natural phenols including Curcumin, Oleuropein, and Resveratrol affect their formation and evolution, and (4) how changes in membrane components including cholesterol and phosphatidylserine affect the function of Aβ pores. Driven progressively by experimental data, we will develop specific models for different variants (based on peak permeability) of each pore type, followed by combining these models into a unified model encompassing both the fast (milliseconds) gating kinetics and slow (tens of minutes and hours) evolution of each Aβ pore type. We will incorporate the effect of modulators and PM components into each model and test how the concurrent presence of different modulators affect Aβ pores' behavior in different cell membranes? We will use these models to perform long simulations (many hours or days) to better understand how pores evolve and how they contribute to overall Ca2+ toxicity as a function of time, spatial arrangement, motility, and ratio of Aβ40, Aβ42, and Aβ43 when inserted into PM and membranes of different intracellular organelles including ER, mitochondria, and lysosomes.

阿尔茨海默病 (AD) 是一种慢性神经退行性疾病，可导致多种认知功能进行性恶化并最终导致死亡，三种淀粉样 β (Aβ) 肽（Aβ40、Aβ42 和 Aβ43）被认为是发病机制中的关键因素。最近的研究结果表明，Aβ 寡聚形式的细胞外和细胞内积累，而不是大的不溶性聚集体，才是可能的病理罪魁祸首，并且它们的毒性是通过在质膜 (PM) 中形成有毒的 Ca2+ 渗透性孔来不受控制地升高胞浆 Ca2+ 介导。然而，关于不同 Aβ 孔类型的功能以及 PM 的哪一个小叶更容易形成孔的详细信息尚不清楚。此外，由于三种类型的肽，这些孔的功能特性表现出显着的多样性和时间依赖性变化。Aβ 的高度异质性和动态性质。毛孔对通过传统的单通道方法研究其致病机制提出了极大的挑战，我们的目标是利用多尺度数据驱动模型与先进的成像技术相结合，填补对 AD 中 Aβ 介导的 Ca2+ 信号干扰的理解的关键空白。使用我们的光学膜片钳技术，我们将监测和比较由细胞外和细胞内 Aβ 寡聚物形成的数百个 Aβ 孔的门控特性和时间依赖性演化。我们将测量和比较电导特性。 ,我们建议在相同条件下对 Aβ40、Aβ42 和 Aβ43 孔进行平行实验，以：（1）阐明并比较它们在包括锌在内的各种调节剂存在下的功能。、铝和铜，(2) 比较 NA7 和 Bexarotene 等 Aβ 孔阻滞剂的效果，(3) 天然酚如何包括姜黄素、橄榄苦苷和白藜芦醇影响它们的形成和进化，以及（4）包括胆固醇和磷脂酰丝氨酸在内的膜成分的变化如何影响Aβ孔的功能在实验数据的逐步推动下，我们将开发针对不同变体的特定模型（基于峰值）。每种孔隙类型的渗透率），然后将这些模型组合成一个统一的模型，其中包含快速（毫秒）的门控动力学和缓慢（数十分钟和数小时）的演化我们将把调节剂和 PM 成分的影响纳入每个模型中，并测试不同调节剂的同时存在如何影响不同细胞膜中 Aβ 孔的行为？我们将使用这些模型进行长时间模拟（多个小时）。或天），以更好地了解孔隙如何演化，以及它们如何影响总体 Ca2+ 毒性，作为时间、空间排列、运动性以及插入 PM 时 Aβ40、Aβ42 和 Aβ43 比例的函数以及不同细胞内细胞器的膜，包括内质网、线粒体和溶酶体。