Proteins Involved in ADAM10 Cleavage from the Plasma Membrane: Investigation Using Molecular Bioengineering Strategies

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition that affects cognitive abilities, causing dementia. With a prevalence of approximately 50 million people worldwide, which is expected to triple by 2050, the significant social and economic impacts make AD a major concern for healthcare systems worldwide. The pathophysiology of AD includes extracellular aggregates of amyloid 5ý (A5ý) as one of its hallmarks. The non-amyloidogenic pathway prevents the formation of aggregation-prone A5ý peptides, where ADAM10 secretase plays a fundamental role. Levels of this protein are altered in the CSF and blood of individuals with AD compared to cognitively unimpaired controls. In this project, we propose a strategy to study an ADAM10 regulatory process that appears unbalanced in AD to cause these differences. To this end, we will employ molecular bioengineering techniques to construct non-cleavable ADAM10 mutant-transfected iPSC cells while silencing wild-type ADAM10. This system will allow us to perform comparative mass spectrometry peptidomics. Investigating this regulatory mechanism will provide insights into the processes and proteins downstream of ADAM10 regulation. Because ADAM10 acts as a sheddase for more than a hundred substrates in addition to APP, the results of this study will have applications beyond the field of AD research.