Modeling Basal Forebrain Cholinergic Vulnerability in Down Syndrome

At a Glance

Down syndrome, also known as trisomy 21, is a condition that impacts the brain’s development of neurological pathways resulting in mild to moderate intellectual disability and middle age onset of Alzheimer’s disease. Basal forebrain cholinergic neurons (BFCNs) are crucial in mediating cognitive performance and memory throughout the lifespan, and they are particularly susceptible to degeneration in individuals with Down syndrome. This project sought to explore the mechanisms that underlie BFCN vulnerability in Down syndrome and looked specifically for observable and age-related markers of BFCN dysfunction in trisomy 21. The results showed similar levels of Alzheimer’s-related proteins in the BFCNs of individuals with and without Down syndrome, despite the fact that people with the condition have an extra gene copy that produces these proteins. The research team identified that trisomy 21 BFCNs had elevated levels of aging markers which may contribute to the intellectual disability and middle age onset of Alzheimer’s disease in people with the condition.

The Challenge

Down syndrome, also known as trisomy 21, is a condition that impacts the brain’s development of neurological pathways resulting in mild to moderate intellectual disability with deficits in attention and memory. Down syndrome is also characterized by middle age onset of Alzheimer’s disease. A critical feature that links cognitive impairment and neurodegeneration in Down syndrome is a population of neurons, or brain cells, that are affected in both processes: basal forebrain cholinergic neurons (BFCNs). BFCNs are crucial in mediating cognitive performance and memory throughout the lifespan, and they are particularly susceptible to degeneration in individuals with Down syndrome. It remains uncertain why this specific group of neurons are vulnerable in these individuals.

Project Goals

This project sought to explore the mechanisms that underlie BFCN vulnerability in Down syndrome with the long-term goals of providing foundational data to identify therapeutic targets and advancing the understanding of Alzheimer’s disease. These goals were addressed through two specific aims:

1. Identify phenotypic, or observable, markers of BFCN dysfunction in trisomy 21
2. Test whether aging exacerbates trisomy 21 BFCN phenotypes.

Results

While the progress of this project was slowed by COVID-19 related restrictions, the team made headway toward their goals. First, a more efficient method to create BFCNs was established using human pluripotent stem cells, which have the potential to develop into many different types of cells in the body. The research team applied this method to generate BFCNs from individuals with and without Down syndrome in order to compare the cell characteristics.

Because individuals with Down syndrome have an extra copy of the 21st chromosome, they also have an extra copy of a gene that produces amyloid precursor protein (APP). The buildup of amyloid protein is thought to play a central role in Alzheimer’s disease, so it is believed that the extra copy of this gene drives the features of the disease in individuals with Down syndrome. However, the researchers found that the ratio of amyloid proteins in Down syndrome and control cells was similar, indicating comparable Alzheimer’s-related changes.

To evaluate how aging affects BFCNs in Down syndrome, the researchers evaluated signs of aging including issues with mitochondria, and damage to epigenetic markers. The results showed that trisomy 21 BFCNs had elevated levels of these markers of aging which may contribute to the intellectual disability and middle age onset of Alzheimer’s disease in people with Down syndrome.