Cells in the blood-brain barrier may control multiple steps in the progression of Alzheimer’s disease—and could serve as potential targets for new treatments, researchers say.
“To my knowledge this is the first study showing how the brain’s vascular system may contribute to the development of Alzheimer’s disease,” says Berislav V. Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine at the University of Southern California and chair for Alzheimer’s Disease Research.
Alzheimer’s disease, a degenerative brain disorder that leads to memory loss and changes in thinking and other brain functions, affects more than 5 million Americans and is the sixth leading cause of death in the United States.
For the new study, published online in Nature Communications, researchers show that pericyte cells may determine the presence of several hallmarks of Alzheimer’s disease.
Brains from Alzheimer’s patients typically have an abnormal accumulation of beta-amyloid protein next to brain cells called plaques; clumps of tau protein inside neurons called neurofibrillary tangles; and extensive neuron loss.
They also often have problems with brain blood vessels reminiscent of vascular dementia, including wounds and a buildup of beta-amyloid protein in vessel walls.
“This study may provide a better understanding of the overlap between Alzheimer’s disease and vascular dementia,” says Roderick Corriveau, a program director at the National Institute of Neurological Diseases and Stroke, which co-funded the study.
Protect the nervous system
Some researchers believe that increases in beta-amyloid are a primary cause of Alzheimer’s, which is supported by genetic studies that link the disease to mutations in amyloid precursor protein (APP), the larger protein from which plaque-forming beta-amyloid molecules are derived.
Previous studies on transgenic mice, however, show that increased beta-amyloid levels only partially reproduce the problems associated with Alzheimer’s.
The animals have memory problems, beta-amyloid plaques in the brain and vascular damage, but none of the neurofibrillary tangles and neuron loss that are hallmarks of the disease.
Found primarily in the blood-brain barrier, pericytes are cells that protect the nervous system from harmful molecules in the blood.
To study how pericytes influence Alzheimer’s disease, researchers crossbred mice genetically engineered to have a form of APP linked to familial Alzheimer’s with ones that have reduced levels of platelet-derived growth factor beta receptor (PDGFRβ), a protein known to control pericyte growth and survival. Previous studies have shown that PDGFRβ mutant mice have fewer pericytes than normal.
Both the APP and PDGFRβ mutant mice had problems with learning and memory. Crossbreeding the mice enhanced these problems. It also induced Alzheimer-like changes in the brain and blood-brain barrier of the mice. The mice had increased beta-amyloid plaque deposition near brain cells and along brain blood vessels.
Surprisingly, the brains of these mice had enhanced neuronal cell death and extensive neurofibrillary tangles in the hippocampus and cerebral cortex, regions that are typically affected in Alzheimer’s patients.
Vascular damage may be key
“Our results suggest that damage to the vascular system may be a critical step in the development of full-blown Alzheimer’s disease pathology,” Zlokovic says.
The researchers also addressed the role of the vascular system in these mice. The crossbred mice had more pericyte death than the PDGFRβ mutant mice and leakage of molecules, such as immunoglobulins, from the blood into the brain.
Other experiments have suggested that pericytes may transport beta-amyloid across the blood-brain barrier and showed that crossbreeding the mice slowed the rate at which beta-amyloid was cleared from the brain.
The results support a “two-hit” vascular hypothesis of Alzheimer’s disease, suggesting that increased beta-amyloid deposition and a breakdown of the blood-brain barrier combine to cause Alzheimer’s.
If true, then the results suggest that pericytes and other blood-brain barrier cells may be new therapeutic targets for the disease, Zlokovic says.
“I think, for future studies, the Alzheimer’s research community should try to focus more attention on understanding the role of the vascular system in disease.”
Researchers at the University of Rochester contributed to the study, which was supported by the National Institute of Neurological Diseases and Stroke and the National Institute on Aging, part of the National Institutes of Health.