The Longest Amyloid-β Precursor Protein Intracellular Domain Produced with Aβ42 Forms β-Sheet-Containing Monomers That Self-Assemble and Are Proteolyzed by Insulin-Degrading Enzyme

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 beta 42 and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Recent clinical trials targeting A beta have failed, suggesting that other polypeptides produced from the amyloid-beta precursor protein (APP) may be involved in AD. An attractive polypeptide is AICD57, the longest APP intracellular domain (AICD) coproduced with A beta 42. Here, we show that AICDS7 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 AICDS7 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 beta but also AICD in the aging brain.