A new study done by USC researchers suggests that a breakdown in the brain’s vascular system and their associated “gatekeeper cells” predates the accumulation of toxic plaques and tangles in the brain that cause Alzheimer’s disease. The findings, published yesterday in Nature Medicine, could offer an earlier target for preventing dementia and Alzheimer’s.
Observing the white matter areas of postmortem Alzheimer’s brains compared to healthy brains in humans, the researchers found approximately 50 percent fewer gatekeeper cells and three times more fibrinogen proteins. To understand what was happening, they set up an experiment using mice lacking in pericytes and compared them to a control group.
Using a diffusion MRI technique, they noticed 50% vessel leakage in mice that were 36 to 48 weeks old, roughly the equivalent of 70 years old in humans. Further investigation revealed reduced cerebral blood flow and increased accumulation of fibrinogen in the brains of mice deficient in gatekeeper cells. At 12 to 16 weeks old, the experimental mice had 10 times more fibrinogen in the corpus callosum, the region that routes motor, sensory and cognitive information to their final destinations.
"Our observations suggest that once pericytes are damaged, blood flow in the brain reduces like a drain that is slowly getting clogged," said Angeliki Maria Nikolakopoulou, co-first author of the study and assistant professor of research at the Zilkha Neurogenetic Institute.
To test the subcortical brain region in the mice, the researchers had the mice run on a specially designed wheel. At 12 to 16 weeks old, the experimental group lacking in pericytes ran at a maximum speed approximately 50% slower than the controls.
Using MRI, they found that white matter changes in mice as early as 12 to 16 weeks old, the human equivalent of 40 years. This indicates that pericytes become compromised early on.
Researchers used an enzyme known to reduce fibrinogen in the blood and brain of mice. White matter volume in the mice returned to 90% of their normal state, and white matter connections were back to 80%.
While future research is needed, these findings offer hope for future interventions that target Alzheimer’s and dementia early on.
Image: Diffusion MRI maps show disrupted white matter connectivity and loss of white matter fiber tracts in 1 year-old pericyte-deficient mice. Image courtesy of Keck School of Medicine of USC/Berislav Zlokovic Lab.