Journal of Biological Chemistry
The transmembrane domain of the amyloid precursor protein is required for anti-amyloidogenic processing by α-secretase ADAM10
Hitschler, L., & Lang, T.
ADAM17, secretases, Alzheimer´s disease, amyloid beta
Neurotoxic amyloid β-peptides (Aβ) are thought to be a causative agent of Alzheimer’s disease in humans. The production of Aβ from amyloid precursor protein (APP) could be diminished by enhancing α-processing; however, the physical interactions between APP and α-secretases are not well understood.
In this study, we employed super-resolution light microscopy to examine in cell-free plasma membranes the abundance and association of APP and α-secretases ADAM10 and ADAM17. We found that both secretase molecules localize similarly closely to APP (within ≤ 50 nm). However, when cross-linking APP with antibodies directed against the GFP-tag of APP, in confocal microscopy we observed that only ADAM10 co-aggregated with APP. Furthermore, we mapped the involved protein domain by using APP variants with an exchanged transmembrane segment or lacking cytoplasmic/extracellular domains. We identified that APP’s transmembrane domain is required for association with α-secretases and, as analysed by Western Blot, for α-processing.
We propose that the APP transmembrane domain interacts either directly or indirectly with ADAM10, but not with ADAM17, explaining the dominant role of ADAM10 in α-processing of APP. Further understanding of this interaction may facilitate the development of a therapeutic strategy based on promoting APP cleavage by α-secretases.