TRISOMY 21 CAUSES A DEFICIT IN LYSOSOMAL CATHEPSINS AND ALTERS APP/Aβ PROCESSING INDEPENDENTLY OF AN EXTRA COPY OF APP

Abstract

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and increases the risk of Alzheimer disease (AD). People who have DS universally develop AD pathology by the age of 40 and the majority develop early-onset dementia (AD-DS). Three copies of the Hsa21 gene APP are sufficient to cause early-onset AD but how trisomy of other Hsa21 genes influences disease development is unclear. We analysed cathepsin activity in patient fibroblasts, post-mortem brain material from people who have DS and AD pathology and a novel mouse model of AD-DS (progeny of the cross of the Tc1 model of Hsa21 trisomy with the J20 APP transgenic model). To understand how changes in cathepsin activity may affect APP and Aβ processing in vitro and in vivo in our AD-DS animal model, we used a combination of pulse-chase analysis, western blotting, immunohistochemistry, ELISA, mass-spectrometry, enzymatic activity assays and in vivo Aβ clearance studies. Additionally we undertook behavioural phenotyping and an aging study of our mouse model of AD-DS to understand how changes in APP/Aβ processing due to trisomy of Hsa21 effect learning and aging. Here we show that triplication of Hsa21 sequences, other than APP, cause cysteine cathepsin deficits that result in failure to activate these proteases in DS. We successfully modelled these enzymatic changes in a novel AD-DS mouse model system, and found that they occur independently of gross-enlargement of the endo-lysosomes. Using our AD-DS mouse model, we show that trisomy of Hsa21 sequences, other than APP, also alter the metabolism of APP/Aβ. These changes decrease the soluble Aβ38/42 ratio and are associated with an increase in Aβ aggregation and deposition, and result in exacerbation of APP/Aβ-associated hyper-activity and specific deficits in two tests of short-term memory. We also show that the trisomy-associated changes in APP/Aβ metabolism we observe occur independently of alterations in α-, β- or γ-secretase activity or changes in the rate of extracellular Aβ-clearance in vivo. We propose that trisomy Hsa21-associated cathepsin deficits are a novel AD-DS pathomechanism that alter APP/Aβ processing and may contribute to the development of AD in people who have DS.