Unclogging blood flow to the brain could open the floodgates for Alzheimer’s treatment
Cognitive impairment and a build-up of abnormal proteins in the brain are better known tell-tale signs of Alzheimer's disease, but other clues may reveal its presence earlier in the piece. Among those is a reduced blood flow to the brain, and scientists from Cornell University believe they have now found an explanation for these blockages, raising new hopes for treatments that target one of the disease's potential root causes.
Just like elsewhere in the body, blood flow into the brain is essential for delivering the oxygen and nutrients needed for cells to do their job properly. When something stems that flow, it can impact cognitive functions like learning and memory, and decades of research has linked this process with the two leading causes of dementia, Alzheimer's disease and vascular dementia.
Pinpointing the exact mechanisms at play would provide invaluable new targets for dementia therapies, but they remain the source of much conjecture. Recent research has pointed to a breakdown in the blood-brain barrier as a factor, for example, with a study published in Neuron last week suggesting leaks allow toxic blood-clotting proteins to gain access and trigger synaptic damage.
A new paper from medical scientists at Cornell University puts forward another explanation. The research stemmed from the discovery of blood clots in the brains of mice with Alzheimer's. More specifically, the researchers found white blood cells were adhering to the inside of capillaries, the brain's smallest blood vessels.
Though they were only found in around two percent of the brain's capillaries, the clots were found to have a disproportionate effect on blood flow, leading to decrease of approximately 20 percent. To explore how the blockages impacted cognitive function, the team treated the animals with antibodies that cleared them away and restored blood flow, and observed improvements within a matter of hours, even in the subjects with more advanced Alzheimer's.
"It is not clear, in humans, what specific impacts reduced brain blood flow has, but the magnitude of the blood flow reduction, around 30 percent on average, is certainly cause for concern," Chris Schaffer, associate professor of Biomedical Engineering at Cornell, explains to New Atlas. "In the Alzheimer's disease mice, we found that increasing blood flow by interfering with the adhesion of white blood cells led to rapid and significant improvement in the performance on memory tasks."
But applying this approach directly to humans would problematic in a few ways. First of all, the antibody used here is not fit for our consumption, and messing with the activity of white blood cells could have unwanted effects on the body's immune system. But the discovery of a major cellular mechanism behind decreased blood flow, and the possibilities it might open up, is what has the scientists excited about the work.
"Prior to our work, it was not appreciated that capillary-level obstructions were the cause of reduced brain blood flow in Alzheimer's disease mouse models," Schaffer tells us. "Much prior work pointed to differences in vascular structure, for example fewer blood vessels and constriction of brain arteries. Each of these mechanisms likely plays some role in altering brain blood flow, but it appears that the adhesion of white blood cells in capillaries is responsible for the majority of the blood flow deficit that Alzheimer's disease mice have relative to control animals."
Schaffer and his team have already identified around 20 drugs that could be used to target the mechanism in humans, some of which are already approved by the FDA. Some of these, however, are designed for intense doses over short periods of time to treat things like heart attacks and strokes. "They weren't really intended to be something that you take for the rest of your life," he says.
Nonetheless, if this same mechanism happens to be at play in human Alzheimer's patients and drugs can be developed to target it, then this could be a "complete game-changer," according to Schaffer. They have already begun screening drugs in mice with Alzheimer's to that effect.
The research was published in the journal Nature Neuroscience.
Source: Cornell University