The Role of Neurexins in Alzheimer’s Disease (Year 2)

Alzheimer’s disease is the most common form of dementia among the elderly. Current studies strongly support the notion that abnormal processing of amyloid beta and accumulation of amyloid beta peptide are the critical events that are associated to the AD pathogenesis. However, the mechanisms of how amyloid beta accumulates at the synapse and induces synaptic deficits in the AD brain largely are unknown. We recently have identified the presynaptic proteins neurexins as amyloid beta precursor protein (APP)-binding proteins by using an unbiased proteomic screen. Biochemical analysis has been applied to further confirm the interaction between neurexins and APP. Importantly, our preliminary results in cells have shown that modification of neurexin levels alters APP processing and amyloid beta generation. Meanwhile, a family-based genome-wide association testing (GWAS) study has determined that all three NRXN genes (NRXN1, NRXN2 and NRXN3) contain susceptibility loci for late-onset AD. Therefore, the goal of this study is to investigate the role of neurexins in the development of amyloid pathology and amyloid beta-induced synaptic dysfunction in AD.