New Molecular Signatures in Alzheimer's Disease

项目摘要 用体内噬菌体展示筛选受限制的多肽文库(包括约108个不同的多肽 序列)已被用作一种新的方法来鉴定存在于 建立阿尔茨海默病(AD)模型的转基因小鼠的大脑。用于此的转基因动物模型 筛选的是J20TG hPPP，它编码淀粉样前体蛋白，与以下两个突变相关 人类公元前。三种特异性识别海马体(疾病的主要部位)的多肽 目前已鉴定出J20小鼠。这些多肽通过静脉注射在海马区蓄积 在患病的大脑区域，而不是在正常产仔的大脑中。先导肽已经被证明是 与AD海马区神经血管单位中激活的星形胶质细胞结合。该多肽还能识别人 AD来源的样本：从人AD iPS细胞分化的内皮细胞结合多肽，而细胞 同样地，从对照组制备的多肽不能与患者的脑切片结合。 有零星的AD。这项应用提出了识别这些多肽的分子靶标(受体)。 这些分子，因为它们将阿尔茨海默病与正常大脑区分开来，可能揭示出AD的新特征 阿尔茨海默病发病机制。它们还应为诊断和治疗目标提供新的机会 广告。这里提出的方法与该领域的当前技术状态有很大的不同，因为目前 这些方法通常专注于靶向错误折叠或异常的蛋白质，如淀粉样斑块。在……里面 相比之下，噬菌体筛选的前三个肽识别血管和血管中的特定变化 AD海马区的血管外神经元组织，并在任何斑块形成之前这样做。 好了！

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. !