Accumulation of BRI2-BRICHOS ectodomain correlates with a decreased clearance of Aβ by insulin degrading enzyme (IDE) in Alzheimer's disease

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 Aβ, but also the levels of secreted insulin degrading enzyme (IDE), an enzyme involved in Aβ clearance. We recently observed increased levels of a 45 kDa BRI2 form as well as BRI2 ectodomain deposits in Aβ plaques in human AD hippocampus, which may affect BRI2 functional activity. Since BRI2 regulated the levels of secreted IDE and subsequent degradation of Aβ in human cell culture models, we explored if BRI2 changes could affect the Aβ degradation capacity of IDE in human hippocampus (n = 28). We observed that IDE is the main enzyme involved in Aβ degradation, and both IDE levels as well as Aβ 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 Aβ 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 Aβ clearance and to the accumulation of Aβ.