Researchers Identify Crucial Cell Death in Down Syndrome

Researchers at the Alzheimer's Center at Temple have identified evidence of a new form of cell death known as necroptosis in the brains of individuals with Down Syndrome, with the corresponding biomarkers providing new clues to potential treatment also for Alzheimer's and other neurodegenerative diseases. 

The findings, published recently in Cell Death and Disease, a publication by the Nature portfolio of journals, are the first to demonstrate the presence of specific proteins associated with this form of cellular death in Down syndrome. The researchers suggest that the role of receptor-interacting protein kinase 1 (RIPK1) and phosphorylated mixed lineage kinase domain-like protein (MLKL) may provide further insight into the mechanisms for neuron loss and offer a treatment target to slow the progression of Down syndrome as well as Alzheimer's disease. The paper, "Necroptosis in Down Syndrome," is available for early access online June 23 ahead of print. 

Down syndrome is the most common genetically defined cause of intellectual disability and is associated with an increased risk of developing Alzheimer's disease-like pathology, including amyloid plaques, tau tangles, synaptic dysfunction, and progressive neuronal loss. While reductions in neuron numbers have been documented in individuals with Down syndrome, the biological mechanisms driving this loss are not well understood. 

Our study provides the first evidence that necroptosis is present in the brains of individuals with Down syndrome and in an animal model of the disease. Our findings suggest that this pathway may contribute to neurodegeneration in Down syndrome and could represent a potential target for future therapeutic interventions."

Domenico Praticò, Professor of Neural Sciences, Temple University's Lewis Katz School of Medicine

Necroptosis is a form of programmed cell death distinct from apoptosis and necrosis. Unlike traditional cell death pathways, necroptosis is often associated with inflammation and has recently been implicated in several neurodegenerative disorders, including Alzheimer's disease.

To investigate whether necroptosis occurs in Down syndrome, the researchers examined brain tissues from a mouse model that reproduces most of the pathologic features found in the human syndrome (Down syndrome mice) and postmortem brain samples from individuals with Down syndrome.

The team found that older Down syndrome mice had significantly elevated levels of several key proteins involved in necroptosis, RIPK1 and MLKL. Analyses showed that these markers were particularly concentrated within neurons. Examination of human brain tissue revealed similar molecular changes, with brains from individuals with Down syndrome showing increased expression of genes associated with the necroptosis pathway.

"Understanding how and why neurons are lost in Down syndrome is essential for developing therapies that may help preserve brain function," Praticò said. "While additional studies are needed to determine the precise role of necroptosis in the disease process, our findings provide a strong rationale for further investigation of this pathway."