It has been evident to scientists for years that Alzheimer’s disease, which affects about five million people in the U.S., is caused by an accumulation of two proteins within the brain. The scientist also knew that there was a missing link. A recent article in Scientific America shows how the University of Alabama’s discovery closes the gap. It also explains why so many treatments have failed.
The Process That Leads to the Death of Cells
Dr. Qin Wang, a neuropharmacology professor at the University of Alabama and the study’s senior author, describes the process that causes Alzheimer’s disease as a “cascade of events.”
Dr. Wang explains that the first “event” is the buildup of clumps (or plaques) of beta-amyloid protein in the brain.
The beta-amyloid then triggers a receptor that in turn reacts to norepinephrine, a naturally-occurring chemical. It is known to affect the brain’s response to events.
When the receptor is activated by both norepinephrine and beta-amyloid there is increased enzyme activity that energizes tau, which is the second protein that has been associated with Alzheimer’s disease. Tau tangles and accumulates inside the brain, causing cell death.
How Does Beta-Amyloid Lead to the Appearance of Tau?
Dr. Wang explains that beta-amyloid takes control of the norepinephrine pathway and activates tau causing toxicity. She said the “cascade” illustrates several reasons for the failure of many Alzheimer’s treatments.
The majority of drugs that were developed over the last few decades were aimed at eliminating beta-amyloid. However, new research indicates that norepinephrine actually increases the destruction wrought by beta-amyloid.
Beta-amyloid, on its own in high doses, kills neurons. If norepinephrine is added to the mix then it takes just one or two percent of beta-amyloid to kill brain cells.
Previous therapies that were aimed at beta-amyloid without targeting the norepinephrine pathway left a sufficient amount of beta-amyloid to do a significant amount of damage.
There are some skeptics, but most agree with Dr. Wang’s analysis.
Although he had not taken part in the study, Dr. Rudolph Tanzi, a molecular genetics expert, is in complete agreement with Dr. Wang. He agreed that for many years scientists assumed that it was beta-amyloid alone that was responsible for the tau tangles as a result of a complex series of events.
In 2014 Dr. Tanzi and the team published a paper in the journal Nature. Using human brain cells that they grew in a lab dish, they refuted a long-held theory.
They claimed that the type of tau found in mice will not have the same effect and will not result in tangles in humans. On the contrary, they demonstrated that beta-amyloid in human cells would cause tau tangles.
Dr. Tanzi and the team set about blocking enzymes (kinases) in an effort to halt the process. They located two enzymes that effectively blocked the GSK3-beta enzyme. This is the same enzyme that Dr. Wang’s team described in their Science Translational Medicine paper. Dr. Tanzi’s study goes further as it shows the way beta-amyloid activates tau’s toxicity.
Dr. Tanzi uses the analogy of brush fires. He suggests that inflammation holds the key to Alzheimer’s and that it triggers the cascade that leads to the disease.
His analogy likens beta-amyloid to a match with tau tangles being the brush fires. GSK3-beta would be the kindling.
In closing, Dr. Tanzi noted that neuroinflammation causes brain cells to die much faster.
Dr. Tanzi and Dr. Wang are both reviewing drugs that prevent beta-amyloid from activating tau tangles. They both have confidence in their data.
