Gradually depletion of BACE1 enzymes has been found in a study conducted by researchers from the Cleveland Clinic Lerner Research Institute to completely reverse the formation of amyloid plaques in the brains of model mice with Alzheimer’s disease improving the rodents’ cognitive functions without unwanted toxicity, raising hopes that drugs to target this enzyme will be able to be successful to treat the disease in humans, as published in the Journal of Experimental Medicine.
Early events in the development of Alzheimer’s disease includes an abnormal buildup of beta-amyloid peptide which can form large plaques in the brain and cause disruptions in the function of neuronal synapses. BACE1/beta-secretase helps produce beta-amyloid peptide by cleaving amyloid precursor protein. Drugs which inhibit beta-secretase are being developed as potential candidates in the treatment of Alzheimer’s disease but beta-secretase controls several important processes by cleaving other proteins, these drugs could have serious side effects.
Model mice completely lacking in beta-secretase suffer from severe neurodevelopmental defects. Researchers conducted this study to investigate whether inhibiting beta-secretase in adults might be less harmful by generating model mice that gradually lost the enzyme as they grew older. It was observed that these model mice developed normally and appeared to remain perfectly healthy as they grew over time.
The model mice were bred to start to develop amyloid plaques and Alzheimer’s disease at 75 days old, the resulting offspring also formed plaques at the same age, even though their beta-secretase levels were close to 50% less than normal. Plaques began to disappear as they continued to age and lose all beta-secretase activity until at a time when at 10 months old they had zero plaques in their brains at all. To the researchers knowledge this is the first display of its kind.
Beta-secretase decreased activity also resulted in lower beta-amyloid peptide levels and reversed all other hallmarks of Alzheimer’s disease including the activation of microglial cells and formation of abnormal neuronal processes without unwanted toxicity. Beta-secretase loss improved memory and learning of the model mice. Electrophysiological recordings from the animals showed that beta-secretase depletion only partially restored synaptic function, which suggests that beta-secretase may be a requirement for optimal cognition and synaptic activity.
It is hopeful that future studies will help to develop strategies to minimize the synaptic impairments that were observed to arise from beta-secretase inhibition to achieve maximum optimal benefits for patients with Alzheimer’s disease.
