Modeling Basal Forebrain Cholinergic Neurons in Down syndrome

摘要 唐氏综合征，或21三体，是一种复杂的神经发育和神经退行性疾病 无序。DS的特征是皮质发育改变，导致出生时智力受损。 以及中年阿尔茨海默病(AD)的病理学。据估计，有40多万人 在美国，患有DS的人每700个活产中就有一个受到影响，DS是最常见的基因 智力残疾的形式，从轻度到中度不等，有缺陷的领域包括 注意力和记忆力。随着DS患者年龄的增长，这些认知功能会随着发育而衰退 公元病理学。在21三体中，将认知障碍和神经变性联系起来的一个关键特征是 在这两个过程中都易受影响的神经元群体：基底前脑胆碱能神经元 (BFCN)。BFCN在调节注意力、记忆和学习方面起着关键作用。退化或 BFCNs的损伤会导致记忆丧失、空间识别能力下降和语言障碍。 这一群体的退化也在不同的人类中得到了很好的记录 神经认知障碍，包括DS和AD。然而，BFCN中涉及的关键分子途径 退化导致的认知、记忆和学习缺陷还没有被很好地理解。这个项目将 探讨同基因对照和DS患者来源的BFCNs的独特差异 诱导多能干细胞(IPSCs)更好地了解其潜在的分子机制 这一子集神经元的易感性，填补了对BFCNs基本理解的一个重大空白。 结果将为确定DS的治疗靶点提供基础数据，并具有 影响我们对其他神经退行性疾病的整体认识，如阿尔茨海默病。

ABSTRACT Down syndrome (DS), or trisomy 21, is both a complex neurodevelopmental and neurodegenerative disorder. DS is characterized by altered cortical development resulting in intellectual impairment at birth and Alzheimer’s disease (AD) pathology in middle age. It is estimated that there are more than 400,000 people living with DS in the U.S. Affecting one in every 700 live births, DS the most common genetic form of intellectual disability, which ranges from mild to moderate with deficits in domains including attention and memory. As individuals with DS age, these cognitive functions decline as they develop AD pathology. A critical feature that links cognitive impairment and neurodegeneration in trisomy 21 is the population of neurons that are susceptible in both processes: basal forebrain cholinergic neurons (BFCN). BFCNs play key roles in regulating attention, memory, and learning. Degeneration or impairment of BFCNs lead to memory loss, decreased spatial recognition, and disturbance in language. Degeneration of this population has also been well documented in a diverse range of human neurocognitive disorders, including DS and AD. However, key molecular pathways involved in BFCN degeneration leading to cognitive, memory and learning deficits aren’t well understood. This project will explore the unique differences of BFCNs derived from both isogenic control and DS human derived induced pluripotent stem cells (iPSCs) to better understand the molecular mechanisms that underlie the susceptibility of this subset of neurons and fill a significant gap in the basic understanding of BFCNs. Results will provide foundational data for identifying therapeutic targets for DS, as well as have an impact on our overall understanding of other neurodegenerative diseases such as AD.