In Silico Modeling of Olfactory Receptor 4M1 and Biochemical Characterization of Novel Ligands in Tauopathy Attenuation

Abstract : Traumatic brain injury (TBI) is a risk factor for several neurodegenerative disorders. We previously reported that abnormal tau processing, a canonical feature in Alzheimer's disease and other tauopathies, may be traced back to abnormal down-regulation of certain ubiquitous olfactory receptors (ORs) in the brain, e.g., the OR4M1 subtype, in subjects with a history of TBI. The objective of this study was to investigate the role of OR in TBI mediated tau pathology and the feasibility of using OR ligands as a novel therapeutic intervention. We built a 3-D OR model and used in silico screening of potential novel ligands from commercial drug libraries to functionally activate OR signaling and eventually attenuate the formation of abnormal tau. Excitingly we found that in vitro activation of OR4M1 with the commercially available ZINC library compound 10915775 led to a significant attenuation of abnormal tau phosphorylation in embryonic cortico-hippocampal neuronal cultures derived from NSE-OR4M1 transgenic mice, possibly through modulation of the JNK signaling pathway. The attenuation of abnormal tau phosphorylation was rather selective since ZINC10915775 significantly decreased tau phosphorylation on tau Ser202/T205 (AT8 eiptope) and tau Thr212/Ser214 (AT100 epitope), but not on tau Ser396/404 (PHF-1 epitope). Moreover, no response of ZINC10915775 was found in control hippocampal neuronal cultures derived from wild type littermates. Our in silico model provides novel means to pharmacologically modulate select ubiquitously expressed ORs in the brain through high affinity ligand activation to prevent and eventually to treat TBI-induced down regulation of ORs and subsequent cascade of tau pathology.