New Molecular Signatures in Alzheimer's Disease

项目摘要 用体内噬菌体展示筛选限制性肽文库（包含约108个不同的 序列）已被用作一种新的方法，以确定特定的分子签名存在于 阿尔茨海默病（AD）模型转基因小鼠的大脑。用于此的转基因动物模型 筛选的是J20 tg hPPP，其编码淀粉样前体蛋白，具有与以下相关的两个突变： 人类AD。三种肽特异性识别海马体（疾病的主要部位）， J20小鼠已被鉴定。这些肽从静脉注射到海马中积累 患病大脑区域，而不是正常窝仔的大脑中。先导肽已被证明 与AD海马神经血管单位中活化的星形胶质细胞结合。该肽还识别人类 AD来源的样品：从人AD iPS细胞分化的内皮细胞结合肽，而细胞 从对照个体类似地制备的肽不能结合，并且肽也结合患者的脑切片 偶尔AD。本申请提出鉴定这些肽的分子靶标（受体）。 这些分子，因为它们区别于正常的大脑AD，可能揭示新的特点， AD的发病机制它们还应提供新的机会， ad.这里提出的方法与本领域的当前技术状态显著不同，因为当前技术状态与本领域的现有技术不同。 方法通常集中于靶向错误折叠或异常的蛋白质如淀粉样蛋白斑。在 相反，来自噬菌体筛选的前三种肽识别血管中的特异性变化， AD海马的血管外神经元组织，并且在任何斑块发展之前这样做。 !

Project Summary Screening with in vivo phage display of constrained peptide libraries (comprising about different 108 sequences) has been employed as a new approach to identify specific molecular signatures present in the brains of transgenic mice that model Alzheimer's Disease (AD). The transgenic animal model used for this screening is the J20 tg hPPP, that encodes amyloid precursor protein with two mutations associated with human AD. Three peptides that specifically recognize the hippocampus (the primary site of the disease) in the J20 mice have been identified. These peptides accumulate from an intravenous injection in the hippocampal area of the diseased brains and not in the brains of normal littermates. The lead peptide has been shown to bind to activated astrocytes in the neurovascular unit of AD hippocampus. This peptide also recognizes human AD-derived samples: Endothelial cells differentiated from human AD iPS cells bind the peptide, whereas cells prepared similarly from a control individual do not, and the peptide also binds to brain sections from a patient with sporadic AD. This application proposes to identify the molecular targets (receptors) for these peptides. These molecules, because they distinguish AD from normal brain, may reveal new features of the pathogenesis of AD. They should also provide new opportunities for diagnostic and therapeutic targeting of AD. The approach proposed here significantly differs from the current state of the art in the field, as current approaches have generally focused on targeting misfolded or aberrant proteins such as amyloid plaques. In contrast, the first three peptides from the phage screens recognize specific changes in the vascular and extravascular neuronal tissue of AD hippocampus, and do so prior to any plaque development. !