CEREBROVASCULAR ABNORMALITIES MAY CONTRIBUTE TO COGNITIVE IMPAIRMENT IN DOWN SYNDROME

Down syndrome (DS) is the most common genetic cause of intellectual disability and is associated with an increased risk of early-onset Alzheimer’s disease (AD). Cerebrovascular abnormalities, including cerebral amyloid angiopathy and microbleeds, are commonly observed in both DS and AD. Moreover, individuals with DS are affected by cerebrovascular diseases such as moyamoya syndrome from early childhood. Given the accumulating evidence of cerebrovascular involvement in AD-related cognitive decline, along with cognitive deficits observed in DS from early childhood, cerebrovascular abnormalities may contribute to cognitive impairment in DS. However, this relationship remains largely unexplored. In a previous study, we identified the most DS-associated gene co-expression module. This module was upregulated in the dorsolateral prefrontal cortex, and its genes were enriched in microglia, astrocytes, and endothelial cells and were involved in immune and vascular functions. To examine the functional role of this module, we overexpressed one of the hub genes, Gene A, in the medial prefrontal cortex of mice and assessed behavioral phenotypes. Gene A overexpression led to reduced social interaction and impaired long-term memory. To elucidate the underlying molecular mechanisms, we performed RNA-sequencing analysis. Differentially expressed genes were predominantly upregulated, enriched in vascular-related cell types, and involved in vascular-related processes, including vascular development, cell adhesion, and extracellular matrix organization. Collectively, these findings suggest that Gene A overexpression may contribute to cerebrovascular abnormalities, such as vascular attenuation, which in turn could lead to cognitive impairment. Our results highlight a potential role of cerebrovascular dysfunction in the development of intellectual disability in DS.