Structural basis for ApoE4-induced Alzheimer's disease

ApoE4 诱导的阿尔茨海默病的结构基础

• 批准号: 10744482
• 负责人: Gregory R Bowman
• 金额: $ 137万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744482
• 关键词: Structural; basis; ApoE4; induced; Alzheimer

Alzheimer's disease (AD) is the 6th leading cause of death in the USA and there are no effective treatments. Moreover, the prevalence of this age-related neurodegenerative disease is likely to increase as the US population ages. Therefore, there is a great need to understand AD and develop therapeutics. ApoE is an appealing target because this lipid transporter is one of the strongest genetic risk factors for AD. ApoE3 is the most common isoform and is considered neutral. Carriers of ApoE4 are up to 15-fold more likely to develop AD, while ApoE2 appears to be protective against AD. Subsequent experiments have confirmed that ApoE4 plays a causal role in AD. However, the mechanism coupling ApoE and AD remains unclear. Strikingly, ApoE4 and ApoE2 each differ from ApoE3 by a single substitution (C112R in ApoE4 and R158C in ApoE2). Neither substitution occurs in a functional site, suggesting they indirectly impact function by altering the protein's conformational preferences. However, characterizing these structural differences remains challenging. Partial crystal structures of the different isoforms are essentially identical and the rest of the protein has largely defied structural characterization because ApoE's role in lipid transport requires it to be partially disordered and prone to oligomerization. This proposal aims to uncover the structural determinants of ApoE-induced neurotoxicity by building and analyzing atomically-detailed Markov state models (MSMs) of neurotoxic and non-toxic variants. The primary focus will be on monomeric, lipid-free ApoE as it is the relevant species for many functional processes, lipid-free ApoE is believed to be the neurotoxic species, and the fluctuations of the monomer are expected to reveal structures whose populations are enhanced/suppressed by binding partners. In Aim 1, new adaptive sampling algorithms will be developed to address the extreme conformational heterogeneity of disordered regions. Then these algorithms will be applied to understand the gross structural properties of representative ApoE variants, such as the extent of domain opening. Computational predictions will be tested with single molecule Förster resonance energy transfer (smFRET) experiments performed with our collaborators. In Aim 2, the allosteric mechanism that couples distant regions of ApoE will be dissected, employing tools once again designed to account for disorder. Resulting insight into the structural differences between neurotoxic and non-toxic isoforms will provide a foundation for the design of new variants to test our models. We will also design `structure correctors' that stabilize non-toxic conformations, providing leads for the future design of drugs that combat AD.

阿尔茨海默氏病（AD）是美国第六大死亡原因，没有有效的治疗方法。 此外，随着美国，这种与年龄相关的神经退行性疾病的流行率可能会增加 人口年龄。因此，非常需要了解广告并发展理论。 Apoe是一个 吸引人的目标是因为这种脂质转运蛋白是AD的强大遗传危险因素之一。 apoe3是 最常见的同工型，被认为是中性的。 APOE4的载体开发广告的可能性高15倍， 而APOE2似乎受到AD的保护。随后的实验已证实APOE4扮演A 因果关系在AD中的作用。但是，耦合APOE和AD的机制尚不清楚。令人惊讶的是，apoe4和 APOE2通过单个替代（APOE4中的C112R和APOE2中的R158C）每个与APOE3不同。两者都不 替代发生在功能部位中，表明它们通过改变蛋白质而间接影响功能 构象偏好。但是，表征这些结构差异仍然是挑战。部分的 不同同工型的晶体结构本质上是相同的，其余的蛋白质已在很大程度上反抗 结构表征是因为ApoE在脂质运输中的作用需要部分弄清并容易发生 进行寡聚。该建议旨在揭示APOE诱导的神经毒性的结构决定者 神经毒性和无毒变体的原子原子马尔可夫州模型（MSMS）的建筑和分析。 主要重点将放在单体，无脂质的apoe上，因为它是许多功能的相关物种 过程，无脂质的APOE被认为是神经毒性物种，单体的波动是 预计将揭示其人口被约束伙伴增强/抑制的结构。在AIM 1中，新 将开发自适应抽样算法来解决极端会议异质性 无序地区。然后，将应用这些算法来了解 代表APOE变体，例如打开域的范围。计算预测将进行测试 通过单分子förster共振能量传递（SMFRET）实验与我们的合作者进行。 在AIM 2中，将阐述APOE的分离区域的变构机制，使用工具一次 再次旨在解释混乱。从而深入了解神经毒性和 无毒的同工型将为设计新变体设计我们的模型提供基础。我们还将设计 稳定无毒构象的“结构校正器”，为未来的药物设计提供潜在客户 战斗广告。