Gamma-Secretase and Myelin: A Paradigm Shift in Brain Disorders

描述(申请人提供)：？-分泌酶是一种膜结合的复合体，由四种蛋白质--早老素、尼古丁、APH-1和Pen-2--组成，可裂解多种底物。？-分泌酶是一种关键的信号分子，控制着几条重要的生化和细胞途径。当它有缺陷时，它在基因和病因上与阿尔茨海默氏症和其他人类疾病有关。淀粉样前体蛋白被分泌酶切割，产生神经毒性的淀粉样多肽，它构成了阿尔茨海默病患者大脑中发现的标志性斑块。Notch被β-分泌酶切割，调节细胞的命运，包括分化、增殖和存活，因此与多种人类疾病有关。ErbB4的裂解调控神经元的髓鞘形成，ErbB4介导的信号通路与精神分裂症有关。这项建议提出的问题是，少突胶质细胞中分泌酶活性的丧失是否会导致与神经功能障碍一致的行为变化。按质量计算，只有大约10%的大脑是神经元。剩下的90%是神经胶质细胞，其中少突胶质细胞占大多数。在发育过程中和损伤后，少突胶质细胞围绕神经元的轴突形成致密的髓鞘，这是一种保护和滋养神经元的脂肪膜，有助于神经电位从神经元到神经元的快速传导。神经生物学传统上专注于研究神经元，以及为什么神经元在神经精神和神经退行性疾病中死亡和死亡。然而，这个项目分析了β-分泌酶如何促进髓鞘形成，以及髓鞘形成缺陷是否单独导致了各种脑部疾病中出现的神经功能障碍。具体目的1是询问在少突胶质细胞中缺乏尼古丁的小鼠是否表现出与神经功能障碍一致的行为。这一目的还询问少突胶质细胞中早老素的丢失是否表现出类似的行为。几种精神活性药物将接受测试，以确定它们是否有能力逆转这些行为变化。特定目的2询问少突胶质细胞中尼古丁的丢失是否会导致这些细胞对其靶轴突髓鞘形成能力的改变。髓鞘形成的变化将在体内(在动物模型的大脑中)和体外(在少突胶质细胞-神经元共培养系统中)进行检测。特指目标3问的是少突胶质细胞中尼古丁的丢失会影响哪些细胞信号通路。在这里，我们将在小鼠模型和共培养系统中分析最重要和最相关的分泌底物--Notch、ErbB4和APP。总之，这里描述的实验将阐明？-分泌酶在调节髓鞘形成中的作用，并回答少突胶质细胞？-分泌酶如何有助于对行为至关重要的神经网络的完整性。因此，这项工作代表了一种新的思考大脑功能和紊乱的方式。

DESCRIPTION (provided by applicant): ?-secretase is a membrane-bound complex of four proteins - presenilin, nicastrin, Aph-1, and Pen-2 - that cleaves a wide variety of substrates. ?-secretase is a key signal molecule that controls several essential biochemical and cellular pathways. When defective, it is genetically and causatively linked to Alzheimer's disease and other human disorders. Cleavage of the amyloid precursor protein by ?-secretase produces the neurotoxic ?-amyloid peptides that comprise the hallmark plaques found in the brains of Alzheimer's patients. Cleavage of Notch by ?-secretase regulates cell fate, including differentiation, proliferation, and survival, and has thus been implicated in multiple human diseases. Cleavage of ErbB4 regulates the myelination of neurons and ErbB4-mediated signaling pathway is linked to schizophrenia. This proposal asks whether loss of ?-secretase activity in oligodendrocytes contributes to behavioral changes consistent with neural dysfunctions. Only approximately 10 percent of the brain is neurons by mass. Glial cells comprise the remaining 90 percent, of which oligodendrocytes comprise the majority. During development and upon injury, oligodendrocytes surround the axons of neurons to form compact myelin, a fatty membrane that protects and nourishes neurons and facilitates the rapid conductance of nerve potentials from neuron to neuron. Neurobiology has traditionally focused on studying neurons, and on why neurons become defunct and die in neuropsychiatric and neurodegenerative disorders. This project, however, analyzes how ?- secretase contributes to myelination and whether defects in myelination alone contribute to the neural dysfunctions seen in various brain diseases. Specific Aim 1 asks whether mice that lack nicastrin in oligodendrocytes exhibit behaviors consistent with neural dysfunctions. This aim also asks whether loss of presenilin from oligodendrocytes exhibits similar behaviors. Several psychoactive drugs will be tested for their ability to reverse these behavioral changes. Specific Aim 2 asks whether the loss of nicastrin from oligodendrocytes results in changes in the ability of these cells to myelinate their target axons. Changes in myelination will be examined both in vivo (in the brains of animal model) and in vitro (in an oligodendrocyte-neuron co-culture system). Specific Aim 3 asks what cellular signaling pathways are affected by loss of nicastrin in oligodendrocytes. Here, the most important and relevant ?-secretase substrates, Notch, ErbB4, and APP, will be analyzed in the mouse model and the co- culture system. Together, the experiments described herein will elucidate ?-secretase's role in regulating myelination and answer how oligodendrocyte ?-secretase contributes to the integrity of neural networks crucial for behaviors. As such this work represents a new way of thinking about brain functions and disorders.