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.