Novel Therapeutic Target Identification through analysis ofConvergent AD and TBI Pathogenic Mechanisms
Technical Report,15 Sep 2018,14 Sep 2019
The Roskamp Institute, Inc. Sarasota United States
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Traumatic Brain Injury TBI, in particular mild TBI mTBI is a major cause of disability in military and in civilian populations, and for many years has been known to be an epigenetic risk factor for Alzheimers Disease AD and other neurodegenerative conditions. However, the precise nature of how TBI leads to or precipitates AD pathogenesis is not understood. To address this problem, we have generated molecular profiles of AD and TBI pathogenesis in mouse models at a range of agestimepoints post-injury respectively, in order to identify molecules and pathways that are common to both AD and TBI. Extensive datasets have been generated, and our comparison and integration of omic profiles clearly points to overlapping disruption of brain lipids and related protein signaling pathways in AD mice with age and TBI mice with time post injury. These include activation of lipid related leukotriene signaling, deficiencies in the eicosanoid signaling, dysfunctional PI3-kinaseAktmTORinsulin and RXRPPAR pathway. Lipids, particularly phospholipids are essential components of neuronal and glial cell membranes and axonal myelin, they modulate protein-protein interaction and cell signal transduction. Thus the TBI-induced pathobiology we have observed may precipitate development of AD and lower the threshold for onset of pathogenic mechanisms. We therefore now propose to validate these convergent AD and TBI mechanisms as novel targets to block the negative sequelae of TBI that lead to AD.
- Anatomy and Physiology