Neurodegeneration in Down syndrome may begin shortly after birth

Signs of neurodegeneration in individuals with Down syndrome may start as early as birth, a critical stage of brain development, a new study shows. The research, from investigators at the Waisman Center, University of Wisconsin–Madison, provides an atlas of early brain development in Down syndrome that could inform potential targeted treatments to address the developmental and degenerative aspects of the condition.

Down syndrome, caused by an extra copy of the 21st chromosome, is the most common genetic cause of intellectual disability. Most individuals with the condition - more than 90 percent - go on to develop Alzheimer's disease in adulthood, but research shows that their brains start undergoing neuroinflammation and neurodegeneration many years before they present signs of dementia. The new study, published in Science, reveals that this process starts as early as zero to three years of age, and involves a widespread dysregulation of genes.

Neuroinflammation is the activation of an immune response in the brain. Chronic inflammation can cause neurons to die, or degenerate, and is a hallmark of neurodegenerative diseases like Alzheimer's.

It was known that these neuroinflammatory processes can be observed at their early 20s, but we are showing in our paper that at birth you already see this very pronounced neuroinflammation and signatures of neurodegeneration while the brain is still developing," says 

André Sousa, assistant professor of neuroscience at UW–Madison and principal investigator of the study

Sousa and colleagues at Waisman are interested in understanding the molecular mechanisms that are disrupted in Down syndrome in early brain development. The first few years of life are a critical period of neurodevelopment, with processes such as maturation of brain cells and formation of synapses - the connections between neurons - peaking at this stage. "If we can identify processes that are disrupted [in this period] it will eventually, hopefully, open the door to try to treat them," Sousa says.

The focus of the study is cells from a region of the brain involved in cognition and working memory called the dorsolateral prefrontal cortex.

Looking inside the nucleus of these brain cells in individuals with Down syndrome, they found changes in gene expression that extend beyond genes on the 21st chromosome. "In general, when we think about Down syndrome, we focus on genes in chromosome 21, because that's the chromosome that's triplicated," says Ryan Risgaard, neuroscience graduate student in Sousa's lab and first author of the study. But they also found disruptions in genes that are not housed on chromosome 21. "I think it really expands our view beyond chromosome 21 to think about other pathways and other chromosomes even," Risgaard adds.

"The root is all in chromosome 21, but downstream, it does affect a lot of other chromosomes that we need to investigate," Sousa explains.

A deeper dive showed that some of the genes dysregulated in Down syndrome are involved in metabolism, inflammation, cell death, and aging. Specifically, these genes appeared to be more active than usual. "I think there's a loop here of neuroinflammation, altered metabolism, and apoptosis (cell death) that all together create a bad mixture," Sousa says.

On the other hand, they found that genes important for cell maturation and communication were less expressed in individuals with Down syndrome compared to controls.

Having identified patterns of gene dysregulation, they went on to identify the specific types of cells that were affected through neurodevelopment. The most noteworthy were glial cells, brain cells that provide support to neurons. All three types of glial cells - oligodendrocytes, astrocytes and microglia - showed pro-inflammatory patterns, including cross-talk between them that creates a loop of neuroinflammation.

"Neuroinflammation at this time point is very critical," Risgaard says. Many neuron-to-neuron connections are being formed during this early postnatal period. Inflammation, he explains, can affect how these synapses are formed and pruned. "And of course, chronic neuroinflammation leads to all sorts of neurodegenerative problems this early," Sousa adds.

These results open the door to future research into the root cause of this inflammation and the Sousa lab is already looking into that. "We don't know yet if the first signal comes from microglia or from astrocytes or from neurons," Sousa says. "What is the first trigger? We still need to work on that." This signal, Sousa mentions, is likely happening in utero.

Identifying the early neuropathology of Down syndrome may lead to specific therapeutic targets against neuroinflammation and neurodegeneration. "We're really hoping that our study will serve as a jumping-off point for other important studies in the Down syndrome field," Risgaard says.