A novel pro-neurogenic therapeutic approach for Alzheimer’s disease based on BRI2 proteolytic fragments

Central nervous system (CNS) neurons have a limited capacity to spontaneously regenerate following injury and in neurodegenerative diseases, which calls for new pro-neurogenic strategies to counteract neurodegeneration. Therefore, understanding neuronal differentiation, function and plasticity by identifying key factors/modulators is a crucial demand to expand the knowledge on CNS ability to reorganize and adapt in res lesions response. BRI2 is a transmembrane protein, which undergoes proteolytic processing, resulting in generation of several secreted peptides whose function remains unknown. Preliminary results pointed to a phenotypic association between BRI2 and its proteolytic processing with neuronal differentiation. Thus, our aim is to explore the contribution of BRI2 proteolytic fragments to neuronal differentiation. In this work, BRI2 processing was evaluated using two cellular models: differentiated SH-S5Y5 cells and primary neuronal cultures (PNC). Further, a recombinant human (rh) BRI2 fragment fused with Myc-tag was produced. SH-SY5Y and PNC were incubated with different concentrations of rhBRI2 fragment, and its cellular uptake was evaluated. The effects of rhBRI2 fragment were assessed by performing a detailed morphometric analysis to characterize cells differentiation phenotypes, and by determining the ability of the fragment to inhibit Aβ42 aggregation. Our results demonstrated that rhBRI2 fragment is internalized by cells in a dose-dependent manner and showed high stability in conditional media. Preliminary evidence suggests that rhBRI2 fragment reduces Aβ42 aggregation. We expect to unveil BRI2 as a neuronal differentiation modulator that hopefully will be proposed as a new therapeutic target to treat neurological conditions characterized by neuronal loss and atrophy, namely Alzheimer´s disease.