Gradual depletion of the enzyme BACE1 totally reverses the formation of amyloid plaques in the brains of mice with Alzheimer’s disease, thereby improving the animals’ cognitive function, researchers from the Cleveland Clinic Lerner Research Institute have found. The study raises hopes that drugs targeting this enzyme will be able to successfully treat Alzheimer’s disease in humans.
One of the earliest events in Alzheimer’s disease is an abnormal buildup of beta-amyloid peptide, which can form large, amyloid plaques in the brain and disrupt the function of neuronal synapses. Also known as beta-secretase, BACE1 helps produce beta-amyloid peptide by cleaving amyloid precursor protein (APP).
Drugs that inhibit BACE1 are therefore being developed as potential Alzheimer’s disease treatments but, because BACE1 controls many important processes by cleaving proteins other than APP, these drugs could have serious side effects.
BACE1 Mouse Model
Mice completely lacking BACE1 suffer severe neurodevelopmental defects.
To investigate whether inhibiting BACE1 in adults might be less harmful, Riqiang Yan and colleagues generated mice that gradually lose this enzyme as they grow older. These mice developed normally and appeared to remain perfectly healthy over time.
The researchers then bred these rodents with mice that start to develop amyloid plaques and Alzheimer’s disease when they are 75 days old. The resulting offspring also formed plaques at this age, even though their BACE1 levels were approximately 50% lower than normal.
Credit: Hu et al., CC-BY
Remarkably, however, the plaques began to disappear as the mice continued to age and lose BACE1 activity, until, at 10 months old, the mice had no plaques in their brains at all.
“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,”
Decreasing BACE1 activity also resulted in lower beta-amyloid peptide levels and reversed other hallmarks of Alzheimer’s disease, such as the activation of microglial cells and the formation of abnormal neuronal processes.
Loss of BACE1 also improved the learning and memory of mice with Alzheimer’s disease. However, when the researchers made electrophysiological recordings of neurons from these animals, they found that depletion of BACE1 only partially restored synaptic function, suggesting that BACE1 may be required for optimal synaptic activity and cognition.
“Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult. 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,”
Reversal of amyloid deposition in an adult AD mouse model produced by sequentially increasing deletion of BACE1. (A) Fixed brain sections from different age groups of the indicated genotypes of mice were stained with antibody 6E10 to label amyloid plaques. A sequential increase in amyloid plaque load in BACE1fl/fl/5xFAD mice from P75, P120, P190, and P300 was visible. Enlarged views show differences in neurons and amyloid plaques, which are indicated by red arrows. No amyloid plaques were observed in P300 BACE1fl/fl/UbcCreER/5xFAD mice, whereas a high load of amyloid plaques was observed in P120 BACE1fl/fl/UbcCreER/5xFAD mice. Bar, 200 µm. (B and C) Numbers of 6E10-positive plaques in the cortex (B) and hippocampus (C) were quantified from six animals in each age group, and mean numbers per section are plotted for comparison (**, P < 0.01; ***, P < 0.001; two-tailed Student’s t test). Plaque load was significantly reduced in BACE1fl/fl/UbcCreER/5xFAD mice older than P120 compared with BACE1fl/fl/5xFAD littermates. Values are expressed as mean ± SEM. Credit: Hu et al., CC-BY
The study was supported by grants from the National Institutes of Health.
Top Image: 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 hallmarks of Alzheimer’s disease are reversed in animals that have gradually lost the BACE1 enzyme (right). Credit: Hu et al., 2018