Mount Sinai studies link APOE4 to brain damage mechanisms

Mount Sinai researchers have reported two studies identifying mechanisms by which the Alzheimer’s disease risk gene APOE4 may damage brain blood vessels and promote abnormal protein buildup. Experiments found that blocking a pathway involved in tissue remodeling reduced vascular scarring and amyloid in aged mice, while a separate study using lab-grown human brain tissue linked APOE4 to impaired clearance of another protein. The findings point to possible research targets, but do not show that any treatment is safe or effective in people. In the study published in Cell, researchers used a map of gene activity in human brain blood vessels to examine how APOE4 affects pericytes, cells that support small vessels and help maintain the blood-brain barrier. They reported that the gene prompts some pericytes to take on characteristics of scar-forming cells. The change was associated with vascular fibrosis and greater amyloid accumulation around vessels, conditions that may compromise blood flow and contribute to neurodegeneration. The team also tested blocking TGFβ signaling, a pathway involved in cellular communication and tissue remodeling.