Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer's Disease
Annual rept. 25 Sep 2012-24 Sep 2013
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK DEPT OF MEDICINE
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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 might 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 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 to screen high affinity ligands. Fifty Seven 57 compounds were identified and clustered into 32 clusters based on their structure similarities. We found significant decrease of the blood OR contents in a rat model of TBI. Outcomes from our study will provide a better understanding of TBI complications and how it is related to AD.
- Anatomy and Physiology
- Medicine and Medical Research