CEMO Seminar "How APP bends, folds and aggregates: the shape of Alzheimer's disease to come"

As it is mentioned in his abstract, “ APP processing has been extensively studied for its central role in Alzheimer’s disease (AD). The amyloidogenic cleavage of APP leads to the production Abeta peptides that aggregate to form senile plaques. APP processing and function are thought to be regulated by homodimerization, which is driven by structural features and particular motifs of the ectodomain and juxtamembrane/transmembrane (JM/TM) domain. We used split protein assays (BiFC and split luciferase) to measure the dimerization level of different APP isoforms and APP C-terminal fragments. BiFC was coupled to FACS and vital confocal imaging. We found that the non-neuronal isoform of (APP751) forms significantly more homodimers than the neuronal one (APP695). APP695 and APP751 differ by the presence of a KPI domain (Kunitz-type Protease Inhibitor) in the extracellular region. By site-directed mutagenesis, we showed that the native folding of KPI is critical for APP751 homodimerization, trafficking along the secretory pathway and amyloidogenic processing. We also identified JM/TM dimerization motifs (GxxxG motifs) as master regulators of the amyloidogenic C-terminal fragments (CTFs) dimerization. Strikingly, these motifs are also critical for Abeta oligomers formation and Abeta fibrils packing. Particular motifs are thus shaping APP structure and orchestrating its various homo-interaction processes (dimerization, oligomerization, fibril formation), which are critical for its physiopathological properties ».

For more information on this subject, this seminar will take place at Pasteur 2 at 12:00.