IMPLICATIONS FOR BACE1 INHIBITOR CLINICAL TRIALS: ADULT CONDITIONAL BACE1 KNOCKOUT MICE EXHIBIT AXONAL ORGANIZATION DEFECTS IN THE HIPPOCAMPUS
J Prev Alz Dis 2019;6(2):78-84
BACE1 is the rate-limiting enzyme for the production of the Aβ peptide that forms amyloid plaques in Alzheimer’s disease (AD). Small molecule inhibitors of BACE1 are being tested in clinical trials for AD, but the safety and efficacy of BACE1 inhibition has yet to be fully explored. Knockout of the Bace1 gene in the germline of mice causes multiple neurological phenotypes, suggesting that BACE1 inhibition could be toxic. However, these phenotypes could be the result of BACE1 deficiency during development rather than due to the lack of BACE1 function in the adult. To address this problem, we generated tamoxifen-inducible conditional BACE1 knockout mice in which the Bace1 gene may be deleted in the whole body of the adult at will. Importantly, the adult conditional BACE1 knockout mice largely lack phenotypes, indicating that many BACE1 functions are not required in the adult organism. However, a germline phenotype was observed after BACE1 knockout in the adult: reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle comprised of axons of dentate gyrus granule cells. The infrapyramidal bundle abnormality correlated with reduced proteolytic processing of the neural cell adhesion protein CHL1 that is involved in axonal guidance. We conclude that BACE1 inhibition in the adult mouse brain does not lead to the phenotypes associated with BACE1 deficiency during embryonic and postnatal development. However, adult conditional BACE1 knockout mice also suggest that BACE1 inhibitor drugs may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory. Here, I review the adult conditional BACE1 knockout results and consider their implications for BACE1 inhibitor clinical trials.
R. Vassar (2019): Implications for BACE1 Inhibitor Clinical Trials: Adult Conditional BACE1 Knockout Mice Exhibit Axonal Organization Defects in the Hippocampus. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.3