Deciphering 􀉶􀍲Secretase mechanisms: providing the underpinnings for novel, rational-based therapeutic approaches

Alzheimer’s disease (AD) is progressive neurodegenerative disorder estimated to affect more than 150 million people by 2050. γ-Secretases (GSECs) are proteases which embedded in the membrane cut several substrates, including the amyloid precursor protein (APP). This cleavage process gained considerable scientific interest as more than 200 mutations in GSEC and around 20 in APP, cause early onset AD. We have recently found that AD-causing weaken the interactions of Gamma secretase and APP during the progressive cleavages and in that way they promote the release of longer amyloid beta fragments. The more the Gamma secretase-APP interaction is undermined, the sooner Alzheimer's disease develops. Thus, our studies point at the stability of GSEC-Substrate (E-S) complexes as central to GSEC function and dysfunction in AD, however, very little is known about the molecular mechanisms that secure GSEC-Substrate (E-S) interactions. Here, we aim to decipher the molecular mechanisms, structural determinants and natural modulators of E-S complexes. The outcome of this fundamental  research will significantly advance our understanding of GSEC function and dysfunction in disease. Furthermore, the generated molecular tools will lay the foundations for - the urgently needed- mechanistic-based strategies aimed at safely grasping GSECs in AD therapy.