APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β40 Aggregation and Toxicity in Alzheimer's Disease

Intracellular C‐terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP‐C31 that is suspected to be involved in the pathology of AD. But details about the role of APP‐C31 in the development of the disease are not known. Here, this work reports that APP‐C31 directly interacts with the N‐terminal and self‐recognition regions of amyloid‐β40 (Aβ40) to form transient adducts, which facilitates the aggregation of both metal‐free and metal‐bound Aβ40 peptides and aggravates their toxicity. Specifically, APP‐C31 increases the perinuclear and intranuclear generation of large Aβ40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aβ40‐induced degeneration of neurites and inflammation are also intensified by APP‐C31 in human neurons and murine brains. This study demonstrates a new function of APP‐C31 as an intracellular promoter of Aβ40 amyloidogenesis in both metal‐free and metal‐present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far. In an Alzheimer's disease (AD)‐affected brain, the releasing of a small peptide, APP‐C31, from the amyloid precursor protein (APP) is increased. The toxicity of APP‐C31 is relatively known, but its role in the pathology of AD remains unclear. These new findings demonstrate that APP‐C31 forms transient adducts with both metal‐free and metal‐bound Aβ40 species and, consequently, promotes their aggregation and toxicity.