Justyna A Dobrowolska Zakaria

Cerebral accumulation of amyloid-beta (Aß) peptides has a critical early role in Alzheimer’s disease (AD) pathogenesis. Cleavage of Amyloid Precursor Protein (APP) by ß-secretase (also called BACE1) produces the sAPPß fragment and this event must occur before Aß may be subsequently released from the APP C-terminal fragment. Although BACE1 levels are increased in AD brain, it is unclear whether BACE1 elevation leads to increased APP cleavage and Aß production in the human CNS. Our preliminary results suggest that newly generated sAPPß is increased in the CSF of amyloid-positive AD subjects. Using methods to measure sAPPß and sAPPa kinetic rates, we propose to determine if and by how much BACE1 activity is increased in late-onset AD (LOAD) subjects and in what subgroups of LOAD the shift toward increased BACE1 processing of APP occurs. We hypothesize that a subgroup of the LOAD and non-demented Amyloid+ populations overproduce Aß because of increased BACE1 activity. We anticipate that kinetic rates of sAPPß and sAPPa as biomarkers of BACE1 activity, together with kinetic rates of Aß isoforms, will allow differentiation of AD subgroups based on different pathogenic mechanisms.