Identification Of Truncated C-Terminal Fragments Of The Alzheimer'S Disease Amyloid Protein Precursor Derived From Sequential Proteolytic Pathways

Recent evidence supports the emerging hypothesis that the amyloid-beta precursor protein C-terminal fragments (APP-CTFs) and dysregulations in both their qualitative and quantitative productions may actively and directly contribute to the neuronal toxicity in early phases of Alzheimer's disease (AD). These new findings revealed the urgent needs and gaps in better understanding the metabolism and full spectrum of APP-CTFs. In this study, we characterized by mass spectrometry the full patterns of APP-CTFs in different cell types and in the brain of an AD APPPS1 mouse model. In these systems, we first discovered a series of 71-80 amino acids long N-terminally truncated APP-CTFs of unknown functions. We next demonstrated that these N-terminally truncated APP-CTFs are sequentially produced by the proteolytic processing of APP-C80, by an as yet unidentified protease. Finally, these N-terminally truncated APP-CTFs are likely protein substrates recognized and processed by the gamma-secretase complex, leading to the production of N-terminally truncated A beta peptides. Together, our findings provide new insights into the metabolism of APP and offer potential new strategies to modulate the production of toxic A beta peptides in AD.