It is well known that Alzheimer's causes progressive decline in memory and thinking. Although cerebrovascular damage has long been recognized, particularly among APOE4 carriers, its mechanisms remained mysterious and it was historically viewed as a secondary consequence of the disease rather than an active driver of its progression.
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First Study (from Cell Journal): APOE4 Converts Supporting Cells into Scar-Forming Cells
The researchers constructed a single-cell transcriptomic atlas of human brain blood vessels a detailed map of gene activity in the cells that form and support blood vessels. They discovered that APOE4 transforms pericytes, which stabilize microvessels and maintain the blood-brain barrier, into myofibroblast-like scar-forming cells. This transformation promoted vascular fibrosis and perivascular amyloid accumulation, potentially impairing blood flow and exacerbating neurodegeneration.
"Vascular damage is not a late consequence of Alzheimer's, but an active biological process caused by APOE4 that may be reversible," said Joel Blanchard, co-corresponding author of the study, adding that the findings "reveal new therapeutic targets."
Second Study (from Cell Stem Cell Journal): Cholesterol Disrupts Protein Clearance
The team utilized "miBrains," 3D human brain tissue derived from induced pluripotent stem cells that contains all major cell types of the brain. They demonstrated that APOE4 causes cholesterol accumulation within astrocytes, which disrupts the lysosomal waste-clearance system (a small organelle acting as the cell's waste disposal center) and reduces their capacity to degrade "alpha-synuclein" (a protein naturally occurring in the brain). Consequently, the protein aggregates and spreads to neurons, forming toxic deposits.
Medical Xpress
