The effects ofCSTBduplication on APP/amyloid-β pathology and cathepsin activity in a mouse model

AbstractPeople with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer’s disease (AD). This is in part because of triplication of a chromosome 21 gene,APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-β that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other thanAPP,when triplicated significantly accelerate amyloid pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases,CYSTATIN B(CSTB)which is proposed to regulate cysteine cathepsin activityin vivo. Here we determined if three copies of the mouse geneCstbis sufficient to modulate beta amyloid (Aβ) accumulation and cathepsin activity in a transgenicAPPmouse model. Duplication ofCstbresulted in an increase in transcriptional and translational levels ofCstbin the mouse cortex but had no effect on the deposition of insoluble Aβ plaques or the levels of soluble or insoluble Aβ42, Aβ40, or Aβ38in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month old mice. These results indicate that the single-gene duplication ofCstbis insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.