Scientists performing studies on genetically engineered mice have found that the cells surrounding blood vessels in the brain, known as pericytes, were found to play an integral role in the mice developing full-blown Alzheimer’s disease – a finding that could lead to pericytes as therapeutic targets for disease treatment.

Current theories behind the formation of Alzheimer’s, presently the leading cause of dementia worldwide, posit that when beta-amyloid plaques accrue in a person’s brain, the disruptive plaques block neuronal communication and eventually degrade the neurons themselves. These plaques also frequently appear beside neurofibrillary tangles and a build-up of a protein called tau. While much is unknown about how Alzheimer’s forms, researchers from the University of Southern California and the University of Rochester Medical Center now argue it may arise from beta-amyloid destruction of pericytes, across what scientists call the “blood-brain barrier.”

The human brain has a stunning system for transporting waste molecules from within its tissues to other parts of the body. This is the blood-brain barrier. As its name implies, it’s essentially the moat that protects the brain from outside pollutants, and vice versa for the surrounding circulatory system. Pericytes, lead researcher Dr. Berislav V. Zlokovic explains, act as the barrier’s gate-keeper. They surround the blood vessels of the brain and determine what is allowed to enter and exit. But as Zlokovic and his colleagues have found, when beta-amyloid plaques destroy these gatekeepers, the potential for neurological damage increases dramatically.

“Our results suggest that damage to the vascular system may be a critical step in the development of full-blown Alzheimer’s disease pathology,” said Dr. Zlokovic in an NIH (National Institutes of Health) news release.

To test past theories of pericyte damage as it related to cognitive decline, the researchers relied on mice that had been genetically engineered. The team crossbred mice that were introduced to the amyloid precursor protein (APP), which is the larger protein from which amyloid plaques are derived, with ones that carried a protein responsible for pericyte growth and survival. Previous studies have shown that mice with this protein, formally known as platelet-derived growth factor beta receptor (PDGFR-beta), had fewer pericytes than normal, decreased brain blood flow, and damage to the blood-brain barrier.

Crossbreeding these two populations of mutant mice slightly worsened the learning and memory problems each had before breeding. More interesting were the increases in amyloid plaque deposition near brain cells and surrounding blood vessels. The mice had increased neurofibrillary tangles and extensive neuronal cell death, both in regions typically affected by Alzheimer’s. Pericytes also died more frequently in the crossbred mice. Meanwhile, the brains of these mice did a poorer job of eliminating amyloid plaques from the cells.

All of this suggested to researchers that diagnosing and treating Alzheimer’s, and some cases of vascular dementia (the second-most common form of the disease), through the examination of pericytes could lead to more effective therapies. If successful in follow-up studies, this mode of treatment would hold promise for the more than five million Americans and the some 36 million people worldwide suffering from the debilitating disease, which robs its victims of memory, cognitive function, and basic thinking skills. There is no cure for Alzheimer’s.

 

Source: Sagare A, Bell R, Zhao Z. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nature Communications. 2013.