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

项目总结/摘要 唐氏综合征（DS）是最常见的染色体疾病，发生率为1/700。是的，由 这是目前已知的导致智力残疾的主要原因。幸运的是，DS人的寿命延长了， 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 由正常的第21对染色体（21三体）的额外染色体引起。21号染色体编码几种 导致AD的基因;最显著的是淀粉样前体蛋白（APP），其被切割形成不同的形式 β-淀粉样蛋白（A β）。AD脑中A β斑块的积累是其定义性病理之一，并且A β斑块也是AD脑中的一种病理。 #21453;人的眼中，与？包括白内障在内的多种眼部异常的发生率要高得多。 频率从年轻的DS患者开始。这些眼部疾病与A型糖尿病有关，A型糖尿病可以 引起透镜上皮层的氧化应激和变性。 为了仔细了解眼睛的贡献和作用，我们建议采用强大的技术， 用于发现可用作适形剂特异性探针的大量纳米抗体（Nbs）的平台 目的：观察A β在眼内（视网膜和透镜组织）的组织学分布。这些NBS将允许我们 识别被忽视的和可能罕见的A β寡聚体构象，这对区分 在DS眼睛中发现的沉积物，可能会对AD产生一些重要的见解。此外，我们的一些NB可能 螯合和溶解某些寡聚体和聚集体的A β，使潜在的发展， 将治疗剂递送到患有DS和AD的人的眼中。我们的具体目标是：（1）发现，生产， 针对A β蛋白构象异构体种类的不同构象验证Nbs，以及（2）测试和验证该面板 使用AD小鼠模型的眼组织和透镜重现DS。这些铌将是有价值的试剂 对于那些学习DS和AD的人来说。

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.