Down syndrome, early cataracts, eye diseases, and beta-amyloid conformers

项目摘要/摘要 唐氏综合征(DS)是最常见的染色体疾病，每700名新生儿中就有1名发生唐氏综合症。它是，由 到目前为止，智力残疾的主要已知原因。谢天谢地，DS人的寿命增加了， 随后出现了几个健康问题，与阿尔茨海默病(AD)有共同之处。DS是 由正常第21对(21三体)的额外染色体引起的。21号染色体编码几个 导致阿尔茨海默病的基因；最显著的是淀粉样前体蛋白(APP)，它被切割形成不同的形式 β-淀粉样蛋白(A)。A斑块在AD脑中的积聚是其决定性的病理之一，A也是 出现在DS患者的眼里。多发性眼畸形，包括白内障，发生的几率要高得多。 对于患有DS的人来说，频率从较小的时候开始。这些眼病与有关，它可以 导致晶状体上皮层氧化应激和退化。 为了仔细了解在眼睛中的贡献和作用，我们建议采用一种强大的技术 用于发现可用作构象特异性探针的大量纳米体板(NB)的平台 目的：研究A在眼(视网膜和晶状体组织)中的组织学分布。这些国家安全局将允许我们 确定被忽视的和可能罕见的A寡聚构象，这对区分可能很重要 在DS眼中发现的沉积物，可能为AD提供了一些重要的见解。此外，我们的一些国家广播公司可能 隔离和溶解A的某些低聚物和聚集体，使新的潜在开发成为可能 治疗药物进入DS和AD患者的眼睛。我们的具体目标是：(1)发现、生产和 针对蛋白构象物种的不同构象验证NBS和(2)测试和验证此面板 用AD小鼠模型的眼组织和晶状体重述DS。这些NBS将是有价值的试剂 对于那些研究DS和AD的人。

PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common chromosomal disorder with an occurrence of 1 in 700 births. It is, by far, the leading known cause of intellectual disability. The longevity of DS people has thankfully increased and several health issues have subsequently emerged, sharing commonality with Alzheimer’s disease (AD). DS is caused by an additional chromosome to the normal 21st pair (Trisomy 21). Chromosome 21 encodes several genes contributing to AD; most notably amyloid precursor protein (APP), which is cleaved to form different forms of beta-amyloid (A). Accumulation of A plaques in the AD brain is one its defining pathologies and A is also present in the eyes of people with DS. Multiple ocular anomalies, including cataracts, occur at a much higher frequency starting at younger ages for people with DS. These eye disorders are associated with A, which can cause oxidative stress and degeneration in the lens epithelial layer. To carefully understand the contribution and role of A in the eye, we propose to adapt a powerful technology platform for the discovery of a large panel of nanobodies (Nbs) that can be used as conformer-specific probes to investigate the histological distribution of A in the eye (retina and lens tissue). These Nbs would allow us to identify overlooked and potentially rare A oligomeric conformers, which could be important to differentiate deposits found in DS eyes, perhaps yielding some important insights for AD. Further, some of our Nbs may sequester and dissolve certain oligomers and aggregates of A, enabling the potential development of novel therapeutics delivered into the eyes of those with DS and AD. Our specific aims are: (1) discover, produce, and validate Nbs against different conformations of A protein conformer species and (2) test and validate this panel of Nbs using eye tissue and lens from AD mouse models recapitulating DS. These Nbs will be valuable reagents for those studying DS and AD.