The effect of BACE1 upregulation on Abeta production was previously investigated in double transgenic mice overexpressing both BACE1 and mutant APP. As expected, Abeta levels were significantly elevated and plaque pathology was seen at an earlier age in the double transgenic mice compared to APP single transgenic mice [14
]. Although BACE1 expression is upregulated in sporadic AD cases [2
], there is no clear evidence that APP is overexpressed in human sporadic AD cases. Therefore, double transgenic mice overexpressing both APP and BACE1 may not be an optimal model to explore the possible effect of BACE1 on Abeta production in sporadic AD patients. In this study, we examined changes in endogenous Abeta levels in response to BACE1 down- and upregulation in mice with physiological APP expression.
Levels of BACE1 protein were gradually reduced in early life, from the newborn period to young adulthood, with concurrent reduction in endogenous mouse Abeta: BACE1 protein and endogenous Abeta were reduced by 70% and 40%, respectively, between 5 days and 16 weeks of age. Levels of APP, a BACE1 substrate, were transiently upregulated during this period as previously reported [17
], but this did not lead to elevation of endogenous Abeta. These findings suggest that BACE1 protein level is a primary factor in determining endogenous Abeta production in early life. Furthermore, this finding suggests that young mice may be more susceptible to pharmacological manipulation of BACE1. Although pharmacokinetics may differ between very young and adult mice complicating analysis, a future study using a brain permeable BACE1 inhibitor may help clarify whether there is a difference in pharmacodynamic response between very young and adult mice.
In contrast to concurrent changes of BACE1 protein and Abeta levels in early life, the impact of BACE1 protein level is very limited in adult mice. Despite significant overexpression of BACE1 protein in transgenic mice (12.7-fold increase compared to BACE1 in wildtype mice), this study demonstrates that endogenous Abeta levels in BACE1 transgenic mice are similar to those of wild-type mice. Abeta levels in adult wild-type mice appear tightly regulated, with a coefficient of variance less than 7% among mice between 10 and 16 weeks of age, based on our unpublished data obtained on over 200 wild-type mice. Although BACE1 expression levels were consistent among BACE1 transgenic mice, Abeta levels were more variable. The variance was not associated with gender or BACE1 expression level. This suggests that BACE1 protein level in adult mice has limited impact on Abeta levels, a conclusion consistent with previous findings in BACE1 homozygous and heterozygous knockout mice. In contrast to complete inactivation of the BACE1 gene, which eliminated Abeta nearly completely [15
], even in mice overexpressing APP [18
], heterozygous BACE1 deletion had only a limited impact. Endogenous Abeta levels were unchanged in BACE1(+/−) mice compared to BACE1(+/+) mice [15
] and Abeta reduction was minimal ( ~12%) and not statistically significant reduced in BACE(+/−)/APP mice at 3 months of age [19
]. Taken together, partial reduction of BACE1 protein level has little effect on Abeta generation in young adult mice.
Nevertheless, although heterozygous BACE(+/−)/APP mice showed minimal Abeta reduction at 3 months of age, the Abeta reduction became significant in aged mice, i.e. with ~90% and ~50% reduction at 13 and 18 months, respectively [19
]. That was considered encouraging, because a partial reduction of BACE1 activity, which might be achievable by pharmacological intervention, could significantly reduce Abeta load in APP over-expressing mice. However, our current data suggest that in conditions of physiological APP expression, the effect or contribution of BACE1 protein level appears not to be rate-limiting in the production of amyloid peptides in young adult mice. Although further studies using aged BACE1 transgenic mice are necessary, our current data suggest that continuous BACE1 inhibition for an extended period may be required to gain a beneficial therapeutic effect in human AD patients. This makes a case for combination therapy, i.e. a BACE1 inhibitor with another class of drugs acting on another arm or another step in the pathological mechanism will be desirable [20