Alzheimer’s disease has been reversed in mice giving hope to human trials

There may be hope for Alzheimer’s patients which will not only lessen the life-changing symptoms but could potentially reverse the disease entirely.

Researchers at the Cleveland Clinic Lerner Research Institute have found that gradually depleting a specific enzyme in the brain could be the key to undoing the damage caused by the debilitating brain disease. There are currently no treatments that stop the progression of Alzheimer’s disease, which is behind the majority of dementia cases and leads to memory loss, disorientation and problems with language.   

In particular, the scientists successfully rollbacked the formation of dangerous amyloid plaques in the brains of mice, paving the way for similar treatments in humans.

The research, published in the Journal of Experimental Medicine, details how the inhibition of the enzyme BACE1 can be used to stop brains from developing amyloid plaques. These plaques are buildups of beta-amyloid peptide which disrupt the functions of synapses and are an early indication of Alzheimer’s disease.

BACE1, also known as beta-secretase, helps produce these plaques by splitting amyloid precursor protein (APP) into beta-amyloid peptide – a process called cleaving. A number of drugs have already been developed as potential ways to inhibit BACE1, and therefore stop amyloid plaques from forming, but the problem is the enzyme also controls a range of important cleaving processes. Cut out BACE1 completely and the brain’s functionality will be seriously damaged.

Scientists as the institute have pioneered an approach that could stop BACE1 from forming plaques without wrecking the basic functionality of the brain.

Lead writer Riqiang Yan worked with colleagues to breed mice that would gradually lose the BACE1 enzyme as they aged. Earlier studies showed that mice with no BACE1 had severe problems in their neurodevelopment so the experiment was set up to glean whether adults would be less negatively affected by reduced levels of the enzyme.

Rodents were first bred to gradually lose the enzyme as they grew older. Once it was established that these animals developed healthily they were bred with other mice that had been bred to develop amyloid plaques when they hit 75 days old. The children would therefore develop Alzheimer’s, but would also reduce BACE1 activity as they aged.

The scientists found that the mice still developed plaques, even though their BACE1 levels were 50% lower than normal. As time passed, however, and BACE1 levels fell further, the plaques began to disappear. By the time the mice were 10 months old, they had no plaques in their brain at all.

(Above: The brain of a 10-month-old mouse with Alzheimer’s disease (left), full of amyloid plaques (red) surrounded by activated microglial cells (green). These hallmarks of Alzheimer’s disease have been reversed (right) in animals that have gradually lost the BACE1 enzyme. Credit: Hu et al., 2018)

“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,” says Yan.

The weaning off of BACE1 activity also led to improved learning and memory in mice with Alzheimer’s disease. However, not all the results were so positive. Electrophysiological recordings of the neurons in the mice revealed that, although the plaques were gone, synaptic functionality had only been partially restored. It is believe that BACE1 may therefore be needed for cognition to work at its most optimal level.  

“Our data suggest that BACE1 is required for optimal synaptic functions,” Yan told Alphr.  “It will be necessary to explore whether long-term use of BACE1 inhibitors will cause unwanted synaptic impairments. Perhaps, a combination of approaches that include both BACE1 inhibitors and synaptic functional enhancer will be more beneficial to Alzheimer’s disease patients.”

BACE1 functionality looks to be a difficult balance to strike, but the hope is that further research can be done to pinpoint the ideal levels of the troublesome enzyme. If that sweet spot is hit, it could signal a new form of treatment for Alzheimer’s in humans.