Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer's Disease

Abstract

Abstract : Traumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer's disease (AD). Abnormal tau processing is a common pathological feature of TBI and AD and tau neuropathology plays a key role in both TBI complications and AD dementia. This study is based on our recent findings of aberrant down-regulation of specific olfactory receptors (OR) as biological indices for TBI and down-regulation of OR TBI biomarkers following TBI may contribute to TBI-related tau neuropathology. We propose that down-regulation of select OR TBI biomarkers in the brain may contribute to the elevation of tau neuropathological phenotypes, thereby promoting the development of AD dementia among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans with exposure to TBI. In Year 1, we found a significant decrease of blood OR contents in a rat model of TBI. We found that activation of OR4M1 by a low affinity ligand resulted in reduced tau phosphorylation via JNK signaling pathway, and a manuscript was published based on this finding. We constructed a virtual 3D structure model for OR4M1 and identified 57 potential ligands for OR activation. In Year 2, we found decreased blood OR content in rats 12 months following blast. We screened the compounds identified from Year 1 in silico screening and confirmed one OR4M1 ligand using cAMP assay. Based on the OR4M1 3D model, we also constructed a 3D model for OR11H1 and performed in silico screening of potential ligands. Outcomes from our study will provide a better understanding of TBI complications and how TBI is related to AD.