APP Biology

Over the last several years our research has focused on elucidating the molecular mechanisms of Aβ generation using structural and functional analyses, particularly the interplay of APP and its processing secretases. As part of this work, we developed and conducted homo-interaction assays and ultimately identified three consecutive GxxxG interaction motifs in the APP transmembrane sequence as playing a significant role in stabilizing dimerization. Most interestingly, disruption or attenuation of the dimerization interface by mutating the GxxxG motifs specifically alters γ-secretase-mediated cleavages, thereby reducing the production of the most toxic form of Aβ, i.e., Aβ42. These findings inspired one of our guiding hypotheses that APP transmembrane sequence dimerization is a risk factor for AD.