BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice

Abstract

β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer’s disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1+/+), heterozygous, and homozygous BACE1 knockout mice (BACE1+/- and BACE1-/-, respectively) were injected with BrdU and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiation of newborn NPCs. We found that NPC proliferation was increased in BACE1-/- mice compared to BACE1+/+ mice, while no difference was observed in NPC survival across genotypes. Differentiation of NPCs to neuronal lineage was impaired in BACE1-/- mice. However, no differences were observed in astrogenesis, in the proportion of immature neurons, or in the production of oligodendrocytes across genotypes. Importantly, corresponding with a decrease in neuronal differentiation in the absence of a complementary increase in an alternate cell fate, BACE1-/- mice were found to have a pool of undifferentiated NPCs in the hippocampus compared to BACE1+/+ and BACE1+/- mice.

Significance Statement The present findings not only demonstrate that BACE1 regulates AHN, but also raise a note of caution that therapeutic inhibition of its enzymatic activity might have potential to produce a pool of adult-generated undifferentiated cells in the hippocampus. Our data strongly suggest that the complete loss of BACE1 activity dysregulates AHN in the adult mouse hippocampus. Alternatively, partial inhibition of BACE1 activity, e.g. in BACE1± mice, may mirror a more suitable therapeutic approach that would not impact AHN or NPC differentiation, for when BACE1 inhibition is being pursued as an effective means of lowering Aβ levels in AD.