Modeling Basal Forebrain Cholinergic Neurons in Down syndrome

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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.