Nara Shin1,2,3, Hyeong-Geug Kim4, Hyo Jung Shin1,3, Sena Kim1, Hyeok Hee Kwon1,3, Hyunjung Baek1,3, Min-Hee Yi5, Enji Zhang1,6, Jwa-Jin Kim1,7, Jinpyo Hong1, Sun Yeul Lee2, Wonhyung Lee2, Ursula L Triantafillu8, Cuk-Seong Kim3,9, Yonghyun Kim8, Dong Woon Kim1,3. 1. 1 Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea. 2. 2 Department of Anesthesia and Pain Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea. 3. 3 Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea. 4. 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. 5. 5 Department of Neurology, Mayo Clinic, Rochester, Minnesota. 6. 6 Department of Anesthesia Medicine, Yanbian University Hospital, Yanbian, China. 7. 7 LES Corporation, Inc., Daejeon, Republic of Korea. 8. 8 Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, Alabama. 9. 9 Department of Physiology, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
Abstract
AIMS: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs. RESULTS: Our rmTBI mouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-α (HIF1α). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFκB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs. INNOVATION: Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model. CONCLUSION: We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE.
AIMS: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs. RESULTS: Our rmTBImouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-α (HIF1α). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFκB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs. INNOVATION: Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model. CONCLUSION: We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE.
Authors: Aydan Kahriman; James Bouley; Thomas W Smith; Daryl A Bosco; Amanda L Woerman; Nils Henninger Journal: Acta Neuropathol Commun Date: 2021-06-29 Impact factor: 7.801
Authors: Matthew M Harper; Danielle Rudd; Kacie J Meyer; Anumantha G Kanthasamy; Vellareddy Anantharam; Andrew A Pieper; Edwin Vázquez-Rosa; Min-Kyoo Shin; Kalyani Chaubey; Yeojung Koh; Lucy P Evans; Alexander G Bassuk; Michael G Anderson; Laura Dutca; Indira T Kudva; Manohar John Journal: Heliyon Date: 2020-02-17