A team of researchers has found that gradually depleting an enzyme called BACE1 reverses the formation of amyloid plaques in the brains of mice with Alzheimer’s disease, thereby improving the animals’ cognitive function. The study was published in the Journal of Experimental Medicine.
An early event in Alzheimer’s is the abnormal buildup of beta-amyloid peptide, which can form large amyloid plaques in the brain and disrupt the function of neuronal synapses. BACE1 helps produce beta-amyloid peptide by cleaving amyloid precursor protein (APP).
Researchers have hypothesized that inhibiting BACE1 could keep the plaques from appearing. However, BACE1 controls many important processes by cleaving proteins other than APP, and mice completely lacking BACE1 have been shown to suffer severe neurodevelopmental defects. For this study, the researchers generated mice that gradually lose this enzyme as they grow older. These mice were shown to develop normally and appeared to remain perfectly healthy over time.
The researchers then bred these rodents with Alzheimer’s mice. The resulting offspring also formed plaques at this age, even though their BACE1 levels were approximately 50% lower than normal. 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.
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.
Article: “BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions”
Reprinted from materials provided by Rockefeller University.