Cathepsin B abundance, activity and microglial localisation in Alzheimer's disease-Down syndrome and early onset Alzheimer's disease; the role of elevated cystatin B

Abstract

Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimers disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimers disease (EOAD). The impact of the additional copy of cystatin B (CSTB) on Alzheimers disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and cystatin B (CSTB) in individuals who had Down syndrome and Alzheimers disease, with disomic individuals who had Alzheimers disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimers disease compared with disomic individuals who had Alzheimers disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B+ cells. We find that the abundance of cystatin B (CSTB) is significantly increased in the brains of individuals who have Down syndrome and Alzheimers disease compared to disomic individuals both with and without Alzheimers disease and we go on to investigate how this impacts enzyme activity in mouse and human cellular preclinical models of Down syndrome.