Influence of myelin basic protein on neuronal A Beta assembly and toxicity

髓磷脂碱性蛋白对神经元 A Beta 组装和毒性的影响

• 批准号: 8484897
• 负责人: William E. Van Nostrand
• 金额: $ 22.79万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484897
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid deposition; Area; Asses; Behavioral; Binding; Biology; Brain; Cell physiology; Cells; Cerebrum; Deposition; Disease; Exhibits; Human; In Vitro; Inflammation; Lead; Ligands; Light; Maps; Mus; Myelin; Myelin Basic Proteins; Myelin Sheath; N-terminal; Neuraxis; Neurons; Outcome; Pathogenesis; Pathological Staging; Pathology; Peptides; Play; Process; Protein Fragment; Protein Precursors; Proteins; Proteolytic Processing; Regulation; Reporting; Research; Role; Senile Plaques; Site; Staging; Structure; Therapeutic Agents; Toxic effect; Transgenic Mice; Work; age related; base; combat; extracellular; in vivo; insight; mouse model; neuroinflammation; neurotoxicity; novel; novel strategies; scaffold; secretase; small molecule

DESCRIPTION (provided by applicant): The amyloid ¿-protein is implicated as a key pathogenic molecule in the pathogenesis of Alzheimer's disease (AD) and related disorders. A¿ possesses the strong propensity to self-assemble into soluble, oligomeric species and ultimately into insoluble, fibrillar structures that deposit in the central nervous system. Although soluble A oligomeric assemblies and A¿ deposits exist largely in the extracellular compartment of the CNS growing evidence suggests that initial assembly stages of A¿ and potential sites for its toxic activities occurs within neurons suggesting that this may be an early site for targeting the disruption of this process. However, our present understanding of what regulates these processes in the CNS, in particular within neurons, remains incomplete. Recently, we identified myelin basic protein (MBP) as a novel factor isolated from brain that can strongly bind to A¿ peptides and potently inhibit their assembly into fibrils and its neurotoxicity. Moreover, this particular function of MBP was mapped to N-terminal residues 1-64 (MBP1-64), a region that is contained in most related Golli proteins as well. In addition to its prominent role in myelin sheat formation, Golli-MBP proteins are present in numerous cells, including neurons, and have been proposed as intracellular multifunctional scaffolds that can bind a number of intracellular proteins and small molecule ligands affecting diverse cellular processes. In light of these points the overall hypothesis of this exploratory proposal is that Golli-MBP proteins interact with intracellular A¿ peptides to influence their assembly, accumulation, and toxicity within neurons and extracellularly in the brain. In the present proposal we plan to implement a multi-faceted approach to investigate how a biologically active MBP fragment interacts with A¿ peptides both in vitro and in vivo to regulate their intracellular and extracellular assembly, deposition, and pathological consequences. First, we will utilize cultured cortical neurons prepared from Tg-5xFAD mice that produce high levels of intracellular and extracellular A¿ peptides in vitro. We will express the MBP1-64 fragment in these neurons to investigate how it influences the fate of intracellular A¿ peptide. Second, we will use the well-characterized Tg-5xFAD mice that exhibit intraneuronal A¿ and develop abundant, age-dependent extracellular A¿ plaque deposits with accompanying neuroinflammation and behavioral deficits. The Tg-5xFAD mice will be crossed with newly generated transgenic mice that express the biologically active MBP1-64 fragment in neurons to investigate its interaction with A¿ peptides and how this might alter pathological outcomes. Completion of these studies will provide new insight into the biology of intracellular Golli-MBP interactions with A¿ that may contribute to the spatial and quantitative regulation of A¿ levels, assembly, and deposition in brain as well as the accompanying downstream pathological consequences.

描述（由应用提供）：淀粉样蛋白蛋白在阿尔茨海默氏病（AD）和相关疾病的发病机理中被视为关键的致病分子。尽管固体A寡聚组件和A沉积物在很大程度上存在于中枢神经系统的细胞外隔室中，但增长的证据表明，A检验的初始组装阶段和其毒性活性的潜在位点发生在神经元内，这表明这可能是针对破坏此过程的早期部位。但是，我们目前对在中枢神经系统中调节这些过程的原因，尤其是在神经元内，仍然是不完整的。最近，我们将髓磷脂碱性蛋白（MBP）鉴定为从大脑中分离出来的新因子，可以强烈结合A肽并可能抑制其组装成原纤维及其神经毒性。此外，将MBP的这种特殊功能映射到N末端残基1-64（MBP1-64），该区域也包含在大多数相关的Golli蛋白中。除了其在髓鞘形成中的重要作用外，包括神经元在内的许多细胞中都存在Golli-MBP蛋白，并已被提出为细胞内多功能支架，这些支架可以结合许多影响多元细胞过程的细胞内蛋白和小分子配体。鉴于这些点，该探索性建议的总体假设是Golli-MBP蛋白与细胞内A肽相互作用，以影响其神经元内的组装，积累和毒性，并在大脑中细胞外。在本提案中，我们计划实施一种多面方法，以研究生物活性的MBP片段如何在体外和体内与A肽相互作用，以调节其细胞内和细胞外组装，沉积和病理后果。首先，我们将利用由TG-5XFAD小鼠制备的培养的皮质神经元，这些神经元在体外产生高水平的细胞内和细胞外A肽。我们将在这些神经元中表达MBP1-64片段，以研究它如何影响细胞内A肽的脂肪。其次，我们将使用特征良好的TG-5XFAD小鼠，该小鼠暴露了神经内神经元，并产生了具有参与神经炎症和行为缺陷的丰富，依赖年龄的细胞外a。斑块沉积物。 TG-5XFAD小鼠将与新生成的转基因小鼠交叉，这些小鼠表达神经元中的生物活性MBP1-64片段，以研究其与A肽的相互作用，以及这如何改变病理结果。这些研究的完成将提供有关细胞内Golli-MBP相互作用与A的生物学的新见解，这可能有助于大脑中A水平，组装和沉积的空间和定量调节以及参与的下游病理后果。

项目成果

The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice.

• DOI: 10.1186/1742-2094-10-134
• 发表时间: 2013-11-05
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Ou-Yang MH;Van Nostrand WE
• 通讯作者: Van Nostrand WE

N-terminal region of myelin basic protein reduces fibrillar amyloid-β deposition in Tg-5xFAD mice.

• DOI: 10.1016/j.neurobiolaging.2014.10.006
• 发表时间: 2015-02
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Ou-Yang MH;Xu F;Liao MC;Davis J;Robinson JK;Van Nostrand WE
• 通讯作者: Van Nostrand WE