Influence of the cellular location of ADAM10 on its activity

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that most affects the elderly population. Classical neuropathological hallmarks of AD include amyloid plaques and neurofibrillary tangles, containing aggregated ²-amyloid (A²) and hyperphosphorylated tau, respectively. In our laboratory, several studies were performed in the area of blood biomarkers for AD, especially focusing on ADAM10 (A Disintegrin and Metallopeptidase) due to its central role in APP (Amyloid Precursor Protein) processing, which has made it an interesting target for therapy and biomarkers studies for AD. The LPN-UNIMI group has publishing unique and interesting results using the ADAM10 collocation technique (via SAP97 and AP2) in order to demonstrate the biology and importance of this molecule for AD pathogenesis. Our previous results demonstrated that plasma ADAM10 levels (~50-55kDa) are increased in elderly with MCI (Mild Cognitive Impairment) and AD, whereas in platelets (60kDa), its levels are decreased. Consequently, this study raised an additional hypothesis related to the presence of two ADAM10 conformations, one soluble and inactive plasma form and the other active membrane-bound platelet form. Thus, the objective of this study is to evaluate whether the enzymatic activity of ADAM10 is dependent on its anchorage to the plasma membrane. To this end during the internship abroad at the LPN-UNIMI laboratory, it is intended to develop and standardize a plasma membrane isolation protocol by cell fractionation in both neuroblastoma cells (SH-SY5Y strain) and primary mice hippocampus. These results are expected to help understand better the biology of the molecule that currently represents a very interesting target for the development of diagnoses and therapies for AD.