APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

Intracellular C -terminal cleavage of the amyloid precursor protein (APP) is elevated in the brain of Alzheimer’s disease (AD). Emerging evidence proposes a pathological relationship between the production of a C -terminal APP fragment, called APP-C31, and the toxicity induced by amyloid-beta (Abeta) that is a major contributor towards AD; however, the interaction between the two peptides and the consequent impact of APP-C31 on Abeta-related toxicity were unknown thus far. Here we report the discovery that APP-C31 facilitates the aggregation of Abeta and aggravates its toxicity at the intracellular level, with escalating neurodegeneration. APP-C31 forms a hetero-dimer with Abeta through the contacts onto the N -terminal and self-recognition regions of Abeta and induces its conformational transition accelerating amyloid fibrillization. APP-C31 promotes the perinuclear and intranuclear deposition of enlarged Abeta aggregates and, consequently, damages the nucleus leading to apoptosis. Abeta-induced degeneration of neurites in human neurons is also intensified by APP-C31. Our studies demonstrate a new function of APP-C31 as an intracellular factor of the proteopathy found in AD.