The precursor protein BRI2 that in its mutated form is associated with British and Danish dementia, can regulate critical processes involved in AD pathogenesis including not only the metabolism of amyloid precursor protein (APP) and formation of A beta, but also the levels of secreted insulin degrading enzyme (IDE), an enzyme involved in A beta clearance. We recently observed increased levels of a 45 kDa BRI2 form as well as BRI2 ectodomain deposits in A beta plaques in human AD hippocampus, which may affect BRI2 functional activity. Since BRI2 regulated the levels of secreted IDE and subsequent degradation of A beta in human cell culture models, we explored if BRI2 changes could affect the A beta degradation capacity of IDE in human hippocampus (n = 28). We observed that IDE is the main enzyme involved in A beta degradation, and both IDE levels as well as A beta degradation tend to be decreased in AD. Interestingly, the levels of the 45 kDa BRI2 form and BRI2 deposits in hippocampal tissue were inversely correlated with IDE protein levels (r = -0.52, p = 0.005; r = -0.4, p = 0.045) and IDE activity (r = -0.5935, p = 0.0004; r = -0.4, p = 0.03). Taken together, the current results suggest a relationship between BRI2 protein changes, IDE activity and A beta levels in human hippocampus. Thus, the formation and accumulation high of molecular weight BRI2 forms observed in AD may impair IDE functioning and consequently lead to impaired A beta clearance and to the accumulation of AP. (C) 2015 Elsevier Ireland Ltd. All rights reserve
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