Negative impact of female sex on outcomes from repetitive mild traumatic brain injury in hTau mice is age dependent: a Chronic Effects of Neurotrauma Consortium study

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice

Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: a Chronic Effects of Neurotrauma Consortium Study

Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI). Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury. Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. However, no noticeable difference was observed between the young and aged groups as initially hypothesized. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice. Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury. These findings suggest differential age-dependent effects in TBI pathobiology

Author Correction: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper

Treatment With Nilvadipine Mitigates Inflammatory Pathology and Improves Spatial Memory in Aged hTau Mice After Repetitive Mild TBI

Mild traumatic brain injury (mTBI) is the most common form of brain trauma worldwide. The effects of mTBI are not well-studied within the elderly population, yet older adults constitute a significant portion of all mTBI patients. Few preclinical studies have focused on the effects of mTBI, or mTBI treatments, in the aged brain, and none have explored repetitive mTBI (r-mTBI). In this study, we have administered our well-characterized 5-injury model (5 r-mTBI) to hTau mice aged 24 months to explore the neurobehavioral and neuropathological outcomes, and the effects of treatment with the dihydropyridine, Nilvadipine. Our previous studies have shown that Nilvadipine inhibits spleen tyrosine kinase (Syk), is effective at reducing inflammation, tau hyperphosphorylation, and amyloid production, and it has recently been investigated in a European Phase III clinical trial for Alzheimer’s disease (AD). In our 24-month-old r-mTBI mice, we observed increased neuroinflammation and a trend toward impaired cognitive performance compared to sham controls. Treatment with Nilvadipine mitigated the TBI-induced inflammatory response in aged r-mTBI animals and significantly improved spatial memory. To our knowledge, this is the only preclinical study focusing on the treatment of r-mTBI in aged, and these results suggest a therapeutic potential of Nilvadipine for consequences of mTBI

APOE Genotype Specific Effects on the Early Neurodegenerative Sequelae Following Chronic Repeated Mild Traumatic Brain Injury

Repeated mild traumatic brain injury (r-mTBI) can potentially manifest into chronic traumatic encephalopathy (CTE). The apolipoprotein E (APOE4) genotype, a well recognized potent genetic risk factor in age-related neurodegenerative diseases such as Alzheimer's disease, has been linked to worse outcome after TBI in individuals who carry this allele. The underlying molecular modifications triggered by APOE genotype following r-mTBI remain elusive. We addressed the influence of APOE genotype on TBI dependent tau pathology in middle-aged mice. Using a previously established experimental mTBI protocol in a new repetitive injury paradigm, we report the pathological changes that occurred following one-month of repetitive injuries in APOE3/4 gene targeted mice. Firstly, pathological assessment demonstrated evidence of microgliosis and astrogliosis in the corpus callosum of injured animals, but there was no APOE dependent genotype effect on injury. However, in the parietal cortex Iba1-immunoreactivity was significantly increased in injured versus sham APOE3 mice, but not in APOE4 mice. No effects were observed in soluble amyloid levels with injury or interaction with genotype. APOE4 mice showed significant increases in the tau conformational marker MC1, neurofilament H, brain phospholipids, and endothelial specific oxidized low density lipoprotein receptor in cortical homogenates obtained from injured mice compared to sham counterparts. This pilot work suggests APOE3 and APOE4 specific effects following injury in a mouse model of r-mTBI. These changes may underlie the molecular changes that trigger the vulnerability and increased risk of developing neurodegenerative diseases in aged individuals exposed to repetitive mTBI

Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress

Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions

Impact Of Age On Acute Post-Tbi Neuropathology In Mice Expressing Humanized Tau: A Chronic Effects Of Neurotrauma Consortium Study

Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI). Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury. Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice. Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury in aged mice. These findings suggest differential age-dependent effects in TBI pathobiology