Expanding Our Understanding of the Role of Bace1

Posted December 13, 2018

New research brings to light cautionary evidence that clinical trials targeting complete inhibition of the enzyme BACE1 may have unintended consequences. BACE1 (β-site amyloid precursor protein cleaving enzyme 1) produces the Aβ42 peptide which, when produced excessively, forms amyloid plaques—one of the hallmarks of Alzheimer’s disease. Inhibition of BACE1 has been actively pursued as a drug target. In this study, the researchers asked the question what role does BACE1 play in the body outside of Aβ42 production? The scientists uncovered a critical role for BACE1 in regulating the growth of new brain cells.

Neural precursor cells generate new neurons in the hippocampus in a process called adult hippocampal neurogenesis. In animal models of Alzheimer’s disease, adult hippocampal neurogenesis is altered contributing to the learning and memory problems of the disease.

The experiments of the current study zeroed in on the impact of reducing BACE1 on the production of new neurons. Whether or not BACE1 regulates adult hippocampal neurogenesis was the focus of the experiments in the present study. The scientists used genetic techniques to knock out the BACE1 gene and then explored whether this change influenced the survival of newborn cells in a region of the hippocampus known for adult hippocampal neurogenesis—the dentate gyrus.

The scientists found that a complete lack of BACE1 impaired the ability of newborn cells to become neurons.

This study highlights the fact that clinical trials aimed at decreasing the activity of BACE1 should not reduce BACE1 completely in order to avoid altering normal neuronal processes such as the birth of new neurons.

The research study is available via eNeuro