Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model.

Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment. One potential treatment option for TON is ST266, a cell-free biological solution containing the secretome of amnion-derived multipotent progenitor (AMP) cells. We investigated the efficacy of intranasal ST266 in a mouse model of TON induced by blunt head trauma. Injured mice treated with a 10-day regimen of ST266 showed an improvement in spatial memory and learning, a significant preservation of retinal ganglion cells, and a decrease in neuropathological markers in the optic nerve, optic tract, and dorsal lateral geniculate nucleus. ST266 treatment effectively downregulated the NLRP3 inflammasome-mediated neuroinflammation pathway after blunt trauma. Overall, treatment with ST266 was shown to improve functional and pathological outcomes in a mouse model of TON, warranting future exploration of ST266 as a cell-free therapeutic candidate for testing in all optic neuropathies.

Impact of gulf war toxic exposures after mild traumatic brain injury.

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.

Subacute and chronic proteomic and phosphoproteomic analyses of a mouse model of traumatic brain injury at two timepoints and comparison with chronic traumatic encephalopathy in human samples.

Repetitive mild traumatic brain injury (r-mTBI) is the most widespread type of brain trauma worldwide. The cumulative injury effect triggers long-lasting pathological and molecular changes that may increase risk of chronic neurodegenerative diseases. R-mTBI is also characterized by changes in the brain proteome, where the majority of molecules altered early post-TBI are different from those altered at more chronic phases. This differentiation may contribute to the heterogeneity of available data on potential therapeutic targets and may present an obstacle in developing effective treatments. Here, we aimed to characterize a proteome profile of r-mTBI in a mouse model at two time points - 3 and 24 weeks post last TBI, as this may be a more relevant therapeutic window for individuals suffering negative consequences of r-mTBI. We identified a great number of proteins and phosphoproteins that remain continuously dysregulated from 3 to 24 weeks. These proteins may serve as effective therapeutic targets for sub-acute and chronic stages of post r-mTBI. We also compared canonical pathway activation associated with either total proteins or phosphoproteins and revealed that they both are upregulated at 24 weeks. However, at 3 weeks post-TBI, only pathways associated with total proteins are upregulated, while pathways driven by phosphoproteins are downregulated. Finally, to assess the translatability of our data, we compared proteomic changes in our mouse model with those reported in autopsied human samples of Chronic Traumatic Encephalopathy (CTE) patients compared to controls. We observed 39 common proteins that were upregulated in both species and 24 common pathways associated with these proteins. These findings support the translational relevance of our mouse model of r-mTBI for successful identification and translation of therapeutic targets.

Influence of traumatic brain injury on extracellular tau elimination at the blood-brain barrier.

Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood-brain barrier (BBB), as the caveolin inhibitor, methyl-ß-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.

A 3-month-delayed treatment with anatabine improves chronic outcomes in two different models of repetitive mild traumatic brain injury in hTau mice.

To date, an overwhelming number of preclinical studies have addressed acute treatment in mild TBI (mTBI) and repetitive mTBI (r-mTBI), whereas, in humans, there often exists a significant time gap between the injury and the first medical intervention. Our study focused on a delayed treatment with anatabine, an anti-inflammatory compound, in hTau mice using two different models of r-mTBI. The rationale for using two models of the same impact but different frequencies (5 hit mTBI over 9 days and 24 hit mTBI over 90 days) was chosen to address the heterogeneity of r-mTBI in clinical population. Following the last injury in each model, three months elapsed before the initiation of treatment. Anatabine was administered in drinking water for 3 months thereafter. Our data demonstrated that a 3-month delayed treatment with anatabine mitigated astrogliosis in both TBI paradigms but improved cognitive functions only in more-frequently-injured mice (24 hit mTBI). We also found that anatabine decreased the phosphorylation of tau protein and NFκB, which were increased after r-mTBI in both models. The ability of anatabine to suppress these mechanisms suggests that delayed treatment can be effective for clinical population of r-mTBI. The discrepancy between the two models with regard to changes in cognitive performance suggests that r-mTBI heterogeneity may influence treatment efficiency and should be considered in therapeutic development.

Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma.

A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders.

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury.

Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor ß, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma.

Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI.

Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (-)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (-)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.

Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model.

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100µg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.

Correction to: Mild TBI Results in a Long-Term Decrease in Circulating Phospholipids in a Mouse Model of Injury.

The original version of this article unfortunately contained a mistake. Gary S. Laco should not be listed as an author in the author group.

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.

Impact of Repetitive Mild Traumatic Brain Injury on Behavioral and Hippocampal Deficits in a Mouse Model of Chronic Stress.

Clinical studies examining the interaction between traumatic brain injury (TBI) and stress-related disorders (e.g., post-traumatic stress disorder) are often complicated by methodological constraints, such as heterogeneity in injury type and severity, time post-trauma, and predisposing risk factors. Developing relevant animal models whereby many variables can be efficiently controlled is thus essential to understanding this elusive relationship. Here, we use our repeated unpredictable stress (RUS) paradigm, in combination with our established mouse model of repetitive mild TBI (r-mTBI), to assess the impact of repeated exposures to these paradigms on behavioral and neurobiological measures. C57BL/6J male mice were exposed to RUS and r-mTBI at 3 and 6 months of age followed by batteries of behavioral testing. Mice were euthanized 10 days and 3 months post-exposure, with brain and plasma samples collected for molecular profiling. The RUS paradigm involved exposure to a predator odor (trimethylthiazoline; TMT) while under restraint, daily unstable social housing, five inescapable footshocks on separate days, and chronic social isolation. Animals receiving r-mTBI ( × 5) and stress were exposed to a single closed-head injury 1 h after each footshock. Stress-alone mice showed significant weight loss, recall of traumatic memories, and anxiety-like and passive stress-coping behavior when compared with control mice. However, in stress+r-mTBI animals, the changes in cued fear memory, anxiety, and stress-coping tests were diminished, possibly due to TBI-induced hyperactivity. We also report complex brain molecular and neuropathological findings. Stress and r-mTBI, either individually or comorbidly, were associated with a chronic reduction in dendritic spine GluN2A/GluN2B ratio in the hippocampus. While stress augmented the r-mTBI-dependent astrogliosis in the corpus callosum, it mitigated r-mTBI-induced increases in hippocampal pro-brain-derived neurotrophic factor. We anticipate that our model will be a good platform to untangle the complex comorbid pathophysiology in stress disorders and r-mTBI.

Converging and Differential Brain Phospholipid Dysregulation in the Pathogenesis of Repetitive Mild Traumatic Brain Injury and Alzheimer's Disease.

Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer's disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing 'pre', 'peri' and 'post' onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.

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 White Matter Degeneration, but No Tau Pathology at One-Year Post-Repetitive Mild Traumatic Brain Injury in a Tau Transgenic Model.

Tau pathology associated with chronic traumatic encephalopathy has been documented in the brains of individuals with a history of repetitive mild traumatic brain injury (r-mTBI). At this stage, the pathobiological role of tau in r-mTBI has not been extensively explored in appropriate pre-clinical models. Here, we describe the acute and chronic behavioral and histopathological effects of single and repetitive mild TBI (five injuries given at 48 h intervals) in young adult (3 months old) hTau mice that express all six isoforms of hTau on a null murine tau background. Animals exposed to r-mTBI showed impaired visuospatial learning in the Barnes maze test that progressively worsened from two weeks to 12 months post-injury, which was also accompanied by significant deficits in visuospatial memory consolidation at 12 months post-injury. In contrast, only marginal changes were observed in visuospatial learning at six and 12 months after single mTBI. Histopathological analyses revealed that hTau mice developed axonal injury, thinning of the corpus callosum, microgliosis and astrogliosis in the white matter at acute and chronic time points after injury. Tau immunohistochemistry and enzyme-linked immunosorbent assay data suggest, however, only transient, injury-dependent increases in phosphorylated tau in the cerebral cortex beneath the impact site and in the CA1/CA3 subregion of the hippocampus after single or r-mTBI. This study implicates white matter degeneration as a prominent feature of survival from mTBI, while the role of tau pathology in the neuropathological sequelae of TBI remains elusive.

Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.

Subchronic Pathobiological Response Following Chronic Repetitive Mild Traumatic Brain Injury in an Aged Preclinical Model of Amyloid Pathogenesis.

Repetitive mild traumatic brain injury (r-mTBI) is a risk factor for Alzheimer disease (AD). The precise nature of how r-mTBI leads to, or precipitates, AD pathogenesis remains unclear. In this study, we explore subchronic effects of chronic r-mTBI (12-impacts) administered over 1-month in aged-PS1/APP mice and littermate controls. We investigate specific mechanisms that may elucidate the molecular link between AD and r-mTBI, focusing primarily on amyloid and tau pathology, amyloid processing, glial activation states, and associated clearance mechanisms. Herein, we demonstrate r-mTBI in aged PS1/APP mice does not augment, glial activation, amyloid burden, or tau pathology (with exception of pS202-positive Tau) 1 month after exposure to the last-injury. However, we observed a decrease in brain soluble Aß42 levels without any appreciable change in peripheral soluble Aß42 levels. This was accompanied by an increase in brain insoluble to soluble Aß42 ratio in injured PS1/APP mice compared with sham injury. A parallel reduction in phagocytic receptor, triggering receptor expressed on myeloid cells 2, was also observed. This study demonstrates very subtle subchronic effects of r-mTBI on a preexisting amyloid pathology background, which may be on a continuum toward a slow and worsening neurodegenerative outcome compared with sham injury, and therefore, have many implications, especially in the elderly population exposed to TBI.

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.