Alzheimer’s disease (AD) is fast becoming a central focus of neuroscience research. To date, not one single clinical trial of medications to treat the disease has been successful.
Researchers know that tangles of beta-amyloid proteins in the brain impair function and memory, but so far the cause of these plaques and treatment to get rid of them has not been found. Recent research from a team at the Cleveland Clinic Lerner Research Institute suggests that eliminating a specific enzyme could reverse the formation of the protein tangles.
The BACE1 enzyme is involved in the creation of the tau deposits in the brain. Before the clumps can form in the brain, a protein called APP (amyloid precursor protein) is released. BACE1 cleaves APP and encourages the rapid formation of beta-amyloid in the brain. Drugs that inhibit the action of BACE1 are, of course, targets in research, but it’s not that simple. BACE1 is involved in a lot of other brain processes, so if it’s eliminated, side effects that cannot be tolerated by patients can occur.
Understanding the beginnings of Alzheimer’s crucial to treating it in humans, because most of the time, the disease is not diagnosed until so much beta-amyloid has been formed that the damage is done, cognitively. Scientists are finding that it might be easier to prevent AD than treat it, once it has passed a certain point.
The team in Cleveland already knew that mice who were genetically engineered to completely lack the BACE1 enzyme had severe neurological defects. Ridding the brain of the BACE1 entirely would not be a viable option. Instead, in the study recently published, mice were created the show normal development early in life, but as they age, they lose the BACE1 enzyme gradually. This way, they were unaltered in their development, but they had lower BACE1 levels when they were older. The mice created this way developed without any health issues.
The researchers then took this mouse variant and bred them to mice who had been created to develop AD when they are about 75 days old. The offspring from these two specifically created mice did still develop Alzheimer’s at the 75-day mark, even though they had 50% less BACE1 enzyme than normal mice. The “ah-ha” moment came when the plaques of beta-amyloid began to disappear from the brains of the mice as they aged. Rather than the disease continuing to progress, it was reversed. By the age of 10 months, the mice were entirely free of beta-amyloid plaques.
Senior author on the study, Riqiang Yan, explained,"To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of Alzheimer's disease mouse models." Yan is a recognized expert in Alzheimer’s research and is now the Chair of Neuroscience at the University of Connecticut. His team reported that in addition to decreasing the protein tangles in the brain, limiting the BACE1 activity also stopped other markers of AD including the activation of microglial cells and the creation of abnormal neural activity.
The mice who had depleted levels of BACE1 also showed improvement in their memory, learning, and hearing. Scans of the neurons did show that full synaptic function was not restored when the plaques disappeared, but it came back partially. More research will be needed to reveal precisely how much BACE1 is required and how much can be eliminated as well as to see if the same process works in humans. Yan summarized the work, saying, “Our data show that BACE1 inhibitors have the potential to treat Alzheimer's disease patients without unwanted toxicity. Future studies should develop strategies to minimize the synaptic impairments arising from significant inhibition of BACE1 to achieve maximal and optimal benefits for Alzheimer's patients.”