The Longest Amyloid-? Precursor Protein Intracellular Domain Produced with A?42 Forms ?-Sheet-Containing Monomers That Self-Assemble and Are Proteolyzed by Insulin-Degrading Enzyme.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease resulting in dementia. It is characterized pathologically by extracellular amyloid plaques composed mainly of deposited A?42 and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Recent clinical trials targeting A? have failed, suggesting that other polypeptides produced from the amyloid-? precursor protein (APP) may be involved in AD. An attractive polypeptide is AICD57, the longest APP intracellular domain (AICD) coproduced with A?42. Here, we show that AICD57 forms micelle-like assemblies that are proteolyzed by insulin-degrading enzyme (IDE), indicating that AICD57 monomers are in dynamic equilibrium with AICD57 assemblies. The N-terminal part of AICD57 monomer is not degraded, but its C-terminal part is hydrolyzed, particularly in the YENPTY motif that has been associated with the hyperphosphorylation of tau. Therefore, sustaining IDE activity well into old age holds promise for regulating levels of not only A? but also AICD in the aging brain.

SUBMITTER: Krasinski CA 

PROVIDER: S-EPMC7074877 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature