A team of researchers from the Cleveland Clinic found that gradually depleting an enzyme called BACE1 blocked the formation of amyloid plaques and improved cognitive function in the brains of mice with Alzheimer’s disease (AD). The study, which was published February 14, 2018 in the Journal of Experimental Medicine*, raises hope that drugs targeting this enzyme will be able to successfully treat AD in humans.
Accumulation of amyloid plaques in the brain is a hallmark of AD, which researchers believe disrupt neuronal synapses, trigger neuronal cell death, and cause memory loss. Amyloid plaques accumulate in the brain because amyloid precursor protein (APP) is cut abnormally – a task carried out by the enzyme beta-secretase (BACE1).
While it is known that lacking the BACE1 enzyme during developmental years causes severe neurodevelopmental defects, the researchers in the current study wanted to investigate whether gradually decreasing BACE1 in adult mice might be less harmful. In this model, the mice developed normally and remained healthy over time. Interestingly, these mice did not have amyloid plaques in the brain or altered neuron function.
The mice that gradually lost BACE1 function over time were then bred with mice that started to develop amyloid plaques and Alzheimer’s disease. The resulting offspring formed amyloid plaques but the plaques began to disappear as the mice continued to age and continue to lose BACE1 activity. Loss of BACE1 function over time also improved the learning and memory of mice with AD.
While other drugs developed to inhibit BACE1 had serious side effects and clinical trials had to end prematurely, this study suggests that amyloid plaques can be completely reversed with declining BACE1 as an adult. This suggests that future studies need to develop strategies to block the activity of BACE1 as an adult to be most effective in the treatment of Alzheimer’s disease patients.
*BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. Xiangyou Hu, Brati Das, Hailong Hou, Wanxia He, Riqiang Yan. DOI: 10.1084/jem.20171831. Published February 14, 2018.
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