INHIBITION OF BACE1 FOR ALZHEIMER’S THERAPY: LESSONS FROM CONDITIONAL DELETION OF BACE1 IN AD MOUSE MODELS

Riqiang Yan

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 USA

Abstract

BACE1, also known as β-secretase, was discovered to be the membrane-anchored aspartyl protease responsible for generating β–amyloid peptides (Aβ) from amyloid precursor protein. However, BACE1 is also required for various neurological functions such as proper myelination of nerves, control of neural stem cell fate determination, neuronal migration, muscle spindle formation, synaptic plasticity, and ion-gated channel activities. Since BACE1 inhibition is currently being tested for the treatment of Alzheimer’s disease (AD) in clinical trials, it is highly important to understand whether inhibition of BACE1 in the adult brain will cause untoward side effects that are specifically related to BACE1 biological functions. To this end, we have generated mouse models in which BACE1 is conditionally deleted through expressed cre-recombinase (cre) by different promoters. Deletion of BACE1 begins during early development in nestin-cre mice, while it begins in adulthood in ubiquitin-cre mice. We compared mouse phenotypes from these two different conditions. We showed that BACE1 deletion during adulthood did not produce significant changes in astrogenesis, neurogenesis, or myelination, unlike those seen in mice with germline deletion of BACE1 or deletion of BACE1 in the early developmental stage. We also examined other phenotypes commonly observed in BACE1-null mice in our conditional mouse models and found that many of the previously reported phenotypes are related to the role of BACE1 during development and are not produced by loss of BACE1 at later stages. However, our results do suggest that inhibition of BACE1 during adulthood will affect synaptic functions, and this potential side effect should be taken into consideration for BACE1 inhibition in AD patients.