Dysfunction of the blood-brain barrier, allowing molecules and cells not normally present in the central nervous system to enter, is one of the features of dementia. If nothing else, this causes inflammation in the brain as the immune system is roused to try to clear out the unwanted materials. Chronic inflammation in the immune cells of the central nervous system is an important part of the progression of neurodegenerative conditions, and in Alzheimer's disease shows up after the initial accumulation of amyloid-β. This sequence of events may be due in part to amyloid-β causing blood-brain barrier dysfunction, though there are certainly numerous other mechanisms to consider.
Amyloid-β plaques, the protein aggregates that form in the brains of Alzheimer's patients, disrupt many brain functions and can kill neurons. They can also damage the blood-brain barrier - the normally tight border that prevents harmful molecules in the bloodstream from entering the brain. Researchers have now developed a tissue model that mimics the effects of amyloid-β on the blood-brain barrier, and used it to show that this damage can lead molecules such as thrombin, a clotting factor normally found in the bloodstream, to enter the brain and cause additional damage to Alzheimer's neurons. "We were able to show clearly in this model that the amyloid-β secreted by Alzheimer's disease cells can actually impair barrier function, and once that is impaired, factors are secreted into the brain tissue that can have adverse effects on neuron health."
The blood vessel cells that make up the blood-brain barrier have many specialized proteins that help them to form tight junctions - cellular structures that act as a strong seal between cells. Alzheimer's patients often experience damage to brain blood vessels caused by amyloid-β proteins, an effect known as cerebral amyloid angiopathy (CAA). It is believed that this damage allows harmful molecules to get into the brain more easily.
Researchers decided to study this phenomenon, and its role in Alzheimer's, by modeling brain and blood vessel tissue on a microfluidic chip. They engineered neurons to produce large amounts of amyloid-β proteins, just like the brain cells of Alzheimer's patients. The researchers then devised a way to grow these cells in a microfluidic channel, where they produce and secrete amyloid-β protein. On the same chip, in a parallel channel, the researchers grew brain endothelial cells, which are the cells that form the blood-brain barrier. An empty channel separated the two channels while each tissue type developed.
After 10 days of cell growth, the researchers added collagen to the central channel separating the two tissue types, which allowed molecules to diffuse from one channel to the other. They found that within three to six days, amyloid-β proteins secreted by the neurons began to accumulate in the endothelial tissue, which led the cells to become leakier. These cells also showed a decline in proteins that form tight junctions, and an increase in enzymes that break down the extracellular matrix that normally surrounds and supports blood vessels. As a result of this breakdown in the blood-brain barrier, thrombin was able to pass from blood flowing through the leaky vessels into the Alzheimer's neurons. Excessive levels of thrombin can harm neurons and lead to cell death.