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Despite the fact that millions of Americans suffer from Alzheimer’s disease, little is known about what causes affected individuals to descend into dementia. Two proteins called tau and beta-amyloid were thought to be involved because they were found in widespread clumps and tangles in the brains of those with Alzheimer’s, but not in those same patterns in those who didn’t have the disease. Unfortunately, it was difficult to tell whether these proteins were the culprits or if they were merely bystanders. Researchers hadn’t developed the techniques to know if they were causing death of neurons in a person’s brain directly or if they indicated a problem elsewhere, somewhat like a traffic jam shows that a car accident is somewhere up ahead.
One of the reasons this problem was so hard to unravel was because it was difficult to create accurate in-lab simulations of human brain tissue. The reason for this is that, unlike skin tissue, neurons don’t just grow in flat sheets. To grow and work as they do in the normal human brain, they need to be able to form a 3-D interconnected lattice. In the past, researchers hadn’t figured out how to do this.
The breakthrough came in a new study out this week when researchers figured out how to layer a gel that allowed neurons to grow three-dimensionally and effectively simulate the growth and death of neurons in the brain of a person with Alzheimer’s.
To make this model, researchers used neurons with gene defects in the genes for presenilin-1 and the amyloid precursor protein. Defects in these genes have been found to increase a person’s risk for developing Alzheimer’s disease and can even lead to a disease called familial Alzheimer’s disease, which runs in families and causes Alzheimer’s at an early age. By using these gene defects, researchers knew that their cells would display the problems typical of a person developing Alzheimer’s.
Sure enough, after six weeks of growth, the cells showed both the tangles of tau protein known to choke the interior of the cell and block functioning and the surrounding plaques of beta-amyloid. The researchers then blocked steps they knew to be involved in the production of beta-amyloid without touching the tau proteins. This prevented the tau tangles from forming in the cell and the subsequent premature death, confirming that beta-amyloid is needed for the development of the deadly tau tangles.
Finally the team looked for enzymes that might be involved in helping the tau tangles to form and found that one enzyme, called GSK3-beta, seemed to add a chemical group to the protein that allowed it to aggregate. When they blocked that enzyme, tangles no longer formed.
Their findings are significant for several reasons. This is the first confirmation of the roles that tau and beta-amyloid play in Alzheimer’s disease, which opens up new avenues of understanding how the disease occurs. Additionally, they provide an enzyme that could be a new target for drugs that would fight the progression of Alzheimer’s disease once detected. Finally, it provides a whole new method for rapidly and cheaply simulating Alzheimer’s disease and unraveling the series of events that lead to Alzheimer’s disease in those who don’t appear to be genetically at risk. Their drug target is likely the first of many still to be discovered.
