P1–018: BACE1 knockout mice fail to put on weight at the same rate as wild type control mice

Beta–site APP Cleaving Enzyme 1 (BACE1) is a key enzyme in the generation of beta–amyloid, a component of senile plaques in the brains of Alzheimer's Disease patients. Inhibition of BACE1 activity in humans is an attractive target for a disease modifying therapy in Alzheimer's Disease, however BACE1 may have also a role unrelated to APP cleavage. Transgenic mice carrying human BACE1 cDNA and knockout mice with endogenous murine BACE1 removed were examined for differences in weight and compared to wild type (wt) controls. A LacZ reporter gene replaced exon 1 of the BACE1 endogenous locus to generate the BACE1 knockout mice and human BACE1 cDNA expression was driven by the Calmodulin kinase 2 promoter in the BACE1 transgenic mice. These mice were weighed as they aged and various tissues were weighed post mortem. BACE1 knockout mice were lighter than wt controls and put on less weight as they aged. This effect was more prevalent in female than male knockout mice. Male but not female BACE1 transgenic mice were heavier and put on more weight than wt controls. No differences were seen in brown adipose tissue weights or body temperature, however peri–genital fat pads were lighter in the knockout mice compared to wt controls. These results suggest an intriguing link between BACE1 and body weight. Despite this phenotype both lines were viable and fertile, however a trend towards increased mortality was seen in the BACE1 knockout mice. An explanation of this phenotype remains to be discovered but may include modulation of appetite or of fat metabolism, perhaps through altered APP processing and beta–amyloid levels although these effects may be unrelated to the role of BACE1 as beta–secretase. Our data might suggest that inhibition of this protease could lead to a change in fat metabolism in treated patients, however one key difference is that we have generated mice which completely lack BACE1 protein or have an excess of BACE1 protein while the administration of a therapeutic BACE1 inhibitor would not change protein levels, at least in the short term, only inhibit its enzyme activity.