Sudad Saman

Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model

Blast exposure is associated with chronic traumatic encephalopathy, impaired neuronal function, and persistent cognitive deficits in blast-exposed military veterans and experimental animals. Blast Brain: An Invisible Injury Revealed Traumatic brain injury (TBI) is the “signature” injury of the conflicts in Afghanistan and Iraq and is associated with psychiatric symptoms and long-term cognitive disability. Recent estimates indicate that TBI may affect 20% of the 2.3 million U.S. servicemen and women deployed since 2001. Chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disorder reported in athletes with multiple concussions, shares clinical features with TBI in military personnel exposed to explosive blast. However, the connection between TBI and CTE has not been explored in depth. In a new study, Goldstein et al. investigate this connection in the first case series of postmortem brains from U.S. military veterans with blast exposure and/or concussive injury. They report evidence for CTE neuropathology in the military veteran brains that is similar to that observed in the brains of young amateur American football players and a professional wrestler. The investigators developed a mouse model of blast neurotrauma that mimics typical blast conditions associated with military blast injury and discovered that blast-exposed mice also demonstrate CTE neuropathology, including tau protein hyperphosphorylation, myelinated axonopathy, microvascular damage, chronic neuroinflammation, and neurodegeneration. Surprisingly, blast-exposed mice developed CTE neuropathology within 2 weeks after exposure to a single blast. In addition, the neuropathology was accompanied by functional deficits, including slowed axonal conduction, reduced activity-dependent long-term synaptic plasticity, and impaired spatial learning and memory that persisted for 1 month after exposure to a single blast. The investigators then showed that blast winds with velocities of more than 330 miles/hour—greater than the most intense wind gust ever recorded on earth—induced oscillating head acceleration of sufficient intensity to injure the brain. The researchers then demonstrated that blast-induced learning and memory deficits in the mice were reduced by immobilizing the head during blast exposure. These findings provide a direct connection between blast TBI and CTE and indicate a primary role for blast wind–induced head acceleration in blast-related neurotrauma and its aftermath. This study also validates a new blast neurotrauma mouse model that will be useful for developing new diagnostics, therapeutics, and rehabilitative strategies for treating blast-related TBI and CTE. Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease.

Background: Tau is secreted unconventionally, possibly explaining increased CSF phosphotau levels in early AD. Results: M1C cells secrete selectively phosphorylated, exosomal tau. These characteristics in early AD CSF tau suggest that CSF tau is secreted, not shed from dead neurons. Conclusion: Tau secretion occurs early and may explain lesion spreading in AD. Significance: Secretion biomarkers may become revolutionary prospective AD diagnostics. Recent demonstrations that the secretion, uptake, and interneuronal transfer of tau can be modulated by disease-associated tau modifications suggest that secretion may be an important element in tau-induced neurodegeneration. Here, we show that much of the tau secreted by M1C cells occurs via exosomal release, a widely characterized mechanism that mediates unconventional secretion of other aggregation-prone proteins (α-synuclein, prion protein, and β-amyloid) in neurodegenerative disease. Exosome-associated tau is also present in human CSF samples and is phosphorylated at Thr-181 (AT270), an established phosphotau biomarker for Alzheimer disease (AD), in both M1C cells and in CSF samples from patients with mild (Braak stage 3) AD. A preliminary analysis of proteins co-purified with tau in secreted exosomes identified several that are known to be involved in disease-associated tau misprocessing. Our results suggest that exosome-mediated secretion of phosphorylated tau may play a significant role in the abnormal processing of tau and in the genesis of elevated CSF tau in early AD.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

The mechanisms underpinning concussion, traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE) are poorly understood. Using neuropathological analyses of brains from teenage athletes, a new mouse model of concussive impact injury, and computational simulations, Tagge et al. show that head injuries can induce TBI and early CTE pathologies independent of concussion.

Proteins Recruited to Exosomes by Tau Overexpression Implicate Novel Cellular Mechanisms Linking Tau Secretion with Alzheimer's Disease

Tau misprocessing to form aggregates and other toxic species has emerged as a major feature in our developing understanding of the etiology and pathogenesis of Alzheimers disease (AD). The significance of tau misprocessing in AD has been further emphasized by recent studies showing that tau can be secreted from neurons via exosomes and may itself be an important agent in the spreading of neurofibrillary lesions within the brain. Tau secretion occurs most readily under disease-associated conditions in cellular models, suggesting that cellular changes responsible for secretion, possibly including tau oligomerization, could play a key role in the propagation of neurofibrillary lesions in neurodegenerative disease. Here we show that overexpression of 4R0N human tau in neuroblastoma cells recruits mitochondrial and axonogenesis-associated proteins relevant to neurodegeneration into the exosomal secretion pathway via distinct mechanisms. The recruitment of mitochondrial proteins appears to be linked to autophagy disruption (exophagy) in multiple neurodegenerative conditions but has few known direct links to AD and tau. By contrast, the involvement of synaptic plasticity and axonogenesis markers is highly specific to both tau and AD and may be relevant to the reactivation of developmental programs involving tau in AD and the recently demonstrated ability of secreted tau to establish tissue distribution gradients in CNS neuropil. We also found a highly significant correlation between genes that are significantly downregulated in multiple forms of AD and proteins that have been recruited to exosomes by tau, which we interpret as strong evidence for the central involvement of tau secretion in AD cytopathogenesis. Our results suggest that multiple cellular mechanisms may link tau secretion to both toxicity and neurofibrillary lesion spreading in AD and other tauopathies.

Death or secretion? The demise of a plausible assumption about CSF-tau in Alzheimer Disease?

Our recent identification of an exosomal route for tau protein secretion1 marks a key similarity between tau and other aggregation-prone proteins implicated in neurodegenerative disease pathogenesis and is to some extent congruent with the popular idea that tau pathology spreads between neurons via a “prionlike” template-mediated protein misfolding mechanism in AD and other tauopathies. However, the observation that much of the phosphotau in CSF samples from early AD patients is exosomal (and thus likely to have been secreted) calls into question a very widely held and plausible assumption - the idea that the elevated CSF-tau in AD is due to the passive release and accumulation of tau in the CSF as a consequence of widespread neuronal death. Here we examine this issue directly and explore some of the broader implications of this study for our understanding of AD pathogenesis and the prospects for improving its diagnosis and treatment.

CONCUSSION, MICROVASCULAR INJURY, AND EARLY TAUOPATHY IN YOUNG ATHLETES AFTER IMPACT HEAD INJURY AND AN IMPACT CONCUSSION MOUSE MODEL

tauopathy in young athletes after impact head injury and an impact concussion mouse model 5 Chad A. Tagge,* Andrew M. Fisher,* Olga V. Minaeva,* Amanda GaudreauBalderrama, Juliet A. Moncaster, Xiao-Lei Zhang, Mark W. Wojnarowicz, Noel Casey, Haiyan Lu, Olga N. Kokiko-Cochran, Sudad Saman, Maria Ericsson, Kristen D. Onos, Ronel Veksler, Vladimir V. Senatorov, Jr, Asami Kondo, Xiao Z. Zhou, Omid Miry, Linnea R. Vose, Katisha R. Gopaul, Chirag Upreti, 10 Christopher J. Nowinski, Robert C. Cantu, Victor E. Alvarez, Audrey M. Hildebrandt, Erich S. Franz, Janusz Konrad, James A. Hamilton, Ning Hua, Yorghos Tripodis, Andrew T. Anderson, Gareth R. Howell, Daniela Kaufer, Garth F. Hall, Kun P. Lu, Richard M. Ransohoff,7,z Robin O. Cleveland, Neil W. Kowall, Thor D. Stein, Bruce T. Lamb, Bertrand R. Huber, 15 William C. Moss, Alon Friedman, Patric K. Stanton, Ann C. McKee, Lee E. Goldstein

Mechanistic pathobiology of acute concussion, traumatic brain injury, and chronic traumatic encephalopathy in mouse models of blast neurotrauma and impact concussion

(active form), while had no effect on the level of Tyrosine-307phosphorylated PP-2A. Unexpectedly, 5-HT1A agonist 8-OHDPAT did not decrease forskolin-induced tau hyperphophorylation. Conclusions:Escitalopram could protect forskolin-induced tau hyperphosphorylation at multiple AD-related sites, and the mechanism involves inactivation of GSK-3b. Our findings suggest that escitalopram could be a promising therapeutic target for AD-like tau hyperphosphorylation, this may support a potential effective role of antidepressants, at least of the SSRI class, in the prevention of dementia associated with depression in patients.

Tau misprocessing leads to nonclassical tau secretion via vesicle release: implications for the spreading of tau lesions in Alzheimer's disease

increased by milton knockdown and involved in the enhancement of tauinduced axon degeneration and tau phosphorylation at AD-related Ser214. Neurofibrillary tangles (NFTs) were not observed in these flies. Conclusions: Since abnormalities in mitochondrial function and localization have been observed in the AD brain, our results suggest that mislocalization of mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD.