Membrane interaction and disruption by the Alzheimer's amyloid-beta peptide

阿尔茨海默氏症淀粉样蛋白-β 肽对膜的相互作用和破坏

基本信息

批准号：
9896738
负责人：
Ayyalusamy Ramamoorthy
金额：
$ 40.59万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2016-08-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896738
关键词：
Adsorption Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology American Amyloid Amyloid Fibrils Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid fibers Atomic Force Microscopy Biochemical Biophysics Brain Mass Calorimetry Cell Death Cell Surface Receptors Cell membrane Cells Cellular Membrane Cholesterol Circular Dichroism Communities Coupled Data Detection Differential Scanning Calorimetry Disease Emotional Environment Family Fluorescence Fluorescence Microscopy Fluorescent Probes Free Radicals Future Gangliosides Generations Goals Heterogeneity In Vitro Intention Ion Channel Ions Isotopes Knowledge Label Link Lipid Bilayers Lipids Measures Membrane Membrane Lipids Memory Loss Metabolic Diseases Metals Methodology Methods Modeling Molecular Monitor Mutation NMR Spectroscopy Nature Nerve Degeneration Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Parkinson Disease Pathogenicity Pathologic Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Play Process Proteins Protons Research Resolution Role Sampling Senile Plaques Societies Spin Labels Structure Techniques Titrations Toxic effect Variant abeta accumulation abeta oligomer abeta toxicity amyloid formation amyloid structure base biophysical analysis brain cell cognitive function drug development early onset experimental study insight membrane assembly misfolded protein molecular dynamics mouse model nanodisk neuron loss number theory prevent protein aggregation protein misfolding solid state nuclear magnetic resonance

项目摘要

Abstract Alzheimer's disease (AD) is a neurodegenerative condition that currently affects more than 5 million Americans. AD is characterized by decreasing memory, loss of cognitive function and an eventual reduction in brain mass. The disease state can be linked to the cleavage of the amyloid precursor protein into smaller fragments - amyloidogenic peptides known as amyloid-β (Aβ). In fact, the formation of amyloid fibrils of the two most common alloforms of Aβ, Aβ1-40 and Aβ1-42, had previously been associated with disease pathology; however, mounting evidence points to misfolded intermediates being responsible for cell death in the Alzheimer's brain. There are a number of theories as to how Aβ elicits toxicity including the generation of free radicals, interaction with metal ions, activation of cell surface receptors, and the disruption of cell membrane integrity. The interaction of Aβ with the cellular membrane is especially significant given the ability of lipid- Aβ interactions to accelerate fibril formation, facilitate the formation of ion channel-like pores, and cause the fragmentation of the lipid membrane. While understanding and characterizing the formation of misfolded intermediates of Aβ in solution is very important (and ongoing), the interaction of Aβ peptides with the membrane has remained elusive and controversial. A lack of data surrounding Aβ-membrane studies is largely due to the difficulties associated with carrying out biochemical and biophysical studies in the presence of lipids, although much insight has been gained by molecular dynamics simulations which have provided a strong basis for experimental studies. In order to determine the mode of membrane-associated toxicity, there remains a need to further characterize the interactions of Aβ with the lipid membrane, determine how these interactions drive membrane disruption, and define the structures formed in the presence of the membrane. Therefore, we propose to investigate the membrane interaction of Aβ through the following aims: 1) Characterization of Aβ misfolding and aggregation in the presence of lipid membranes; 2) Atomistic resolution structure determination of Aβ in a membrane environment by solid-state NMR spectroscopy. In addition to a variety of biophysical experiments, a combination of solution and solid-state NMR techniques and molecular dynamics simulations will be used to successfully accomplish the goals of the proposed study. High-resolution insights gained from the proposed studies will guide the development of drugs to stop the neuronal death. Although the proposed study is focused on Aβ, the outcome will be of importance to other amyloid-linked diseases such as Parkinson's disease and Type II diabetes which have similar proteinopathies.

抽象的阿尔茨海默氏病（AD）是一种神经退行性疾病，目前影响超过500万美国人。 AD的特征是记忆力降低，认知功能的丧失和降低事件脑质量。疾病状态可以与淀粉样前体蛋白的裂解相关片段 - 称为淀粉样蛋白β（Aβ）的淀粉样蛋白生成肽。实际上，形成了 Aβ，Aβ1-40和Aβ1-42的两种最常见的同型与疾病病理有关。但是，越来越多的证据表明，错误折叠的中间体负责导致细胞死亡阿尔茨海默氏症的大脑。关于Aβ如何引起毒性，包括自由的产生，有许多理论自由基，与金属离子的相互作用，细胞表面受体的激活以及细胞膜的破坏正直。鉴于脂质Aβ的能力，Aβ与细胞膜的相互作用尤为重要相互作用以加速原纤维形成，促进形成离子通道样孔，并导致脂质膜的碎裂。同时理解和表征错误折叠的形成 Aβ在溶液中的中间体非常重要（并且正在进行），Aβ肽与膜仍然难以捉摸且引起争议。缺乏围绕Aβ-膜研究的数据很大程度上是由于在脂质存在下进行生化和生物物理研究的困难，尽管分子动力学模拟获得了很多洞察力，这些模拟提供了强大的基础用于实验研究。为了确定与膜相关毒性的模式，仍然存在需要进一步表征Aβ与脂质膜的相互作用，确定这些相互作用如何驱动膜破坏，并定义在膜存在下形成的结构。因此，我们通过以下目的研究Aβ的膜相互作用的建议：1）Aβ的表征在脂质膜的存在下折叠和聚集； 2）原子分辨率结构确定通过固态NMR光谱法在膜环境中的Aβ。除了多种生物物理实验，溶液和固态NMR技术与分子动力学模拟的组合将被用来成功实现拟议研究的目标。从中获得的高分辨率见解拟议的研究将指导药物的开发以阻止神经元死亡。尽管拟议的研究将指导药物的发展以阻止神经元死亡。研究的重点是Aβ，结果将对其他淀粉样蛋白疾病（例如帕金森氏病和具有相似蛋白质的II型糖尿病。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Spontaneous Lipid Nanodisc Fomation by Amphiphilic Polymethacrylate Copolymers.

DOI：
10.1021/jacs.7b10591
发表时间：
2017-12-27
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Yasuhara K;Arakida J;Ravula T;Ramadugu SK;Sahoo B;Kikuchi JI;Ramamoorthy A
通讯作者：
Ramamoorthy A

Small molecule induced toxic human-IAPP species characterized by NMR.

DOI：
10.1039/d0cc04803h
发表时间：
2020-11-07
期刊：
Chemical communications (Cambridge, England)
影响因子：
0
作者：
Cox SJ ;Rodriguez Camargo DC ;Lee YH ;Dubini RCA ;Rovó P ;Ivanova MI ;Padmini V ;Reif B ;Ramamoorthy A
通讯作者：
Ramamoorthy A

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

对开发化学工具以控制阿尔茨海默氏病个体和相互相关的病理特征的结构和机制见解。

DOI：
10.1002/chem.201605401
发表时间：
2017
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Lee,HyuckJin;Korshavn,KyleJ;Nam,Younwoo;Kang,Juhye;Paul,ThomasJ;Kerr,RichardA;Youn,IlSeung;Ozbil,Mehmet;Kim,KwangS;Ruotolo,BrandonT;Prabhakar,Rajeev;Ramamoorthy,Ayyalusamy;Lim,MiHee
通讯作者：
Lim,MiHee

Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.

DOI：
10.7554/elife.31226
发表时间：
2017-11-17
期刊：
eLife
影响因子：
7.7
作者：
Rodriguez Camargo DC;Korshavn KJ;Jussupow A;Raltchev K;Goricanec D;Fleisch M;Sarkar R;Xue K;Aichler M;Mettenleiter G;Walch AK;Camilloni C;Hagn F;Reif B;Ramamoorthy A
通讯作者：
Ramamoorthy A

Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time