02/19/2018

A team of Cleveland Clinic Lerner Research Institute researchers led by Riqiang Yan, PhD, Department of Neurosciences, found that gradually depleting an enzyme called BACE1 completely reverses the formation of amyloid plaques in the brain and improves cognitive function in mice with Alzheimer's disease, correcting both the brain pathology and symptoms most commonly associated with the disease. The study, which was published February 14 in the Journal of Experimental Medicine, raises hopes that drugs targeting this enzyme will successfully treat Alzheimer's in humans.

One of the earliest events in Alzheimer's disease, which happens long before symptoms first present, is an abnormal buildup of beta-amyloid peptide, which can form large amyloid plaques in the brain and disrupt the function of neuronal synapses. BACE1, also known as beta-secretase, contributes to beta-amyloid peptide production by cleaving amyloid precursor protein (APP). A key hypothesis in the field, then, is that drugs that inhibit BACE1 activity may help prevent and treat Alzheimer's. But because BACE1 cleaves proteins other than APP, and therefore controls many important processes in the body, there is concern that BACE1-inhibiting drugs may have serious side effects.

Mice completely lacking BACE1 suffer severe neurodevelopmental defects. To investigate whether inhibiting BACE1 over time rather than completely blocking it might be less harmful, Dr. Yan and colleagues developed a novel model in which mice gradually lose this enzyme as they grow older. The mice developed normally and appeared to remain perfectly healthy over time.

The researchers bred these rodents with a strain of mice that start to develop amyloid plaques when they are 75 days old. The resulting offspring also formed plaques at this age, even though their levels of BACE1 were approximately 50% lower than normal. Remarkably, however, the plaques began to disappear as the mice continued to age and lose BACE1 activity. At 10 months old, the mice had no plaques in their brains at all.

Decreasing BACE1 activity also lowered beta-amyloid peptide levels and reversed other pathological hallmarks of the disease, including activation of microglial cells and abnormal neuronal processes. It also improved learning and memory in the mice. It's important to note, however, that electrophysiological recordings of the mice's neurons revealed that BACE1 depletion only partially restored synaptic function, suggesting that BACE1 may be required for optimal synaptic activity and cognition.

The study provides genetic evidence to suggest that preformed amyloid deposits can be completely reversed after sequential and increased deletion of BACE1 in adults. While future studies are needed to develop strategies to minimize synaptic impairments associated with BACE1 inhibition, this research offers great reason to hope that BACE1 inhibitors may be the key to treating Alzheimer's disease.

Xiang-You Hu, MD, PhD, is first author on the study, which was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging.

This story is modified from a EurekAlert published by Rockefeller University Press.

Photo: The brain of a 10-month-old mouse with Alzheimer's disease (left) is full of amyloid plaques (red) surrounded by activated microglial cells (green). These pathologies are reversed in animals that have gradually lost the BACE1 enzyme (right).