Age-dependent differential expression of BACE splice variants in brain regions of tg2576 mice

Plaques found in the brains of patients suffering from Alzheimer's disease (AD) mainly consist of β-amyloid (Aβ), which is produced by sequential cleaving of amyloid precursor protein (APP) by two proteolytic enzymes, β- and γ-secretases. Any change in the fine balance between these enzymes and their substrate may contribute to the etio-pathogenesis of AD. Indeed, the protein level and enzymatic activity of β-secretase (BACE), but not its mRNA level, were found elevated in brain areas of AD patients who suffer a high load of Aβ plaque formation. Similarly, increased BACE activity but no mRNA change was observed in a transgenic mouse model of AD, tg2576, in which over expression of the Swedish mutated human APP leads to Aβ plaque formation and learning deficits. Based on the recent demonstration of four BACE splice variants with different enzymatic activity, the discrepancy between BACE activity and mRNA expression may be explained by the altered BACE alternative splicing. To test this hypothesis, we studied the expression of all BACE splice variants in different brain areas of tg2576 mice at age of 4 months and 1 year old. We found developmental and regional differences between wild-type and tg2576 mice. Our results indicate that over expression of APP in tg2576 mice leads to the altered alternative splicing of BACE and the increase of its enzymatically more active splice variant (I-501).