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      APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes

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          Abstract

          After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E ( APOE) are known to increase risk for developing Alzheimer’s disease, however there is controversy from human and rodent studies as to whether ApoE4 is a risk factor for worse outcomes after brain trauma. To resolve these conflicting studies we have explored the effect of the human APOE4 gene in a reproducible mouse model that mimics common human injuries. We have investigated cellular and behavioral outcomes in genetically engineered human APOE targeted replacement (TR) mice following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. Relative to injured APOE3 TR mice, injured APOE4 TR mice had more inflammation, neurodegeneration, apoptosis, p-tau, and activated microglia and less total brain-derived neurotrophic factor (BDNF) in the cortex and/or hippocampus at 1 and/or 21 days post-injury. We utilized a novel personalized approach to treating APOE4 susceptible mice by administering Bryostatin-1, which improved cellular as well as motor and cognitive behavior outcomes at 1 DPI in the APOE4 injured mice. This study demonstrates that APOE4 is a risk factor for poor outcomes after rmTBI and highlights how personalized therapeutics can be a powerful treatment option.

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          Apoptosis: a review of programmed cell death.

          The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
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            Traumatic Brain Injury–Related Emergency Department Visits, Hospitalizations, and Deaths — United States, 2007 and 2013

            Problem/Condition Traumatic brain injury (TBI) has short- and long-term adverse clinical outcomes, including death and disability. TBI can be caused by a number of principal mechanisms, including motor-vehicle crashes, falls, and assaults. This report describes the estimated incidence of TBI-related emergency department (ED) visits, hospitalizations, and deaths during 2013 and makes comparisons to similar estimates from 2007. Reporting Period 2007 and 2013. Description of System State-based administrative health care data were used to calculate estimates of TBI-related ED visits and hospitalizations by principal mechanism of injury, age group, sex, and injury intent. Categories of injury intent included unintentional (motor-vehicle crashes, falls, being struck by or against an object, mechanism unspecified), intentional (self-harm and assault/homicide), and undetermined intent. These health records come from the Healthcare Cost and Utilization Project’s National Emergency Department Sample and National Inpatient Sample. TBI-related death analyses used CDC multiple-cause-of-death public-use data files, which contain death certificate data from all 50 states and the District of Columbia. Results In 2013, a total of approximately 2.8 million TBI-related ED visits, hospitalizations, and deaths (TBI-EDHDs) occurred in the United States. This consisted of approximately 2.5 million TBI-related ED visits, approximately 282,000 TBI-related hospitalizations, and approximately 56,000 TBI-related deaths. TBIs were diagnosed in nearly 2.8 million (1.9%) of the approximately 149 million total injury- and noninjury-related EDHDs that occurred in the United States during 2013. Rates of TBI-EDHDs varied by age, with the highest rates observed among persons aged ≥75 years (2,232.2 per 100,000 population), 0–4 years (1,591.5), and 15–24 years (1,080.7). Overall, males had higher age-adjusted rates of TBI-EDHDs (959.0) compared with females (810.8) and the most common principal mechanisms of injury for all age groups included falls (413.2, age-adjusted), being struck by or against an object (142.1, age-adjusted), and motor-vehicle crashes (121.7, age-adjusted). The age-adjusted rate of ED visits was higher in 2013 (787.1) versus 2007 (534.4), with fall-related TBIs among persons aged ≥75 years accounting for 17.9% of the increase in the number of TBI-related ED visits. The number and rate of TBI-related hospitalizations also increased among persons aged ≥75 years (from 356.9 in 2007 to 454.4 in 2013), primarily because of falls. Whereas motor-vehicle crashes were the leading cause of TBI-related deaths in 2007 in both number and rate, in 2013, intentional self-harm was the leading cause in number and rate. The overall age-adjusted rate of TBI-related deaths for all ages decreased from 17.9 in 2007 to 17.0 in 2013; however, age-adjusted TBI-related death rates attributable to falls increased from 3.8 in 2007 to 4.5 in 2013, primarily among older adults. Although the age-adjusted rate of TBI-related deaths attributable to motor-vehicle crashes decreased from 5.0 in 2007 to 3.4 in 2013, the age-adjusted rate of TBI-related ED visits attributable to motor-vehicle crashes increased from 83.8 in 2007 to 99.5 in 2013. The age-adjusted rate of TBI-related hospitalizations attributable to motor-vehicle crashes decreased from 23.5 in 2007 to 18.8 in 2013. Interpretation Progress has been made to prevent motor-vehicle crashes, resulting in a decrease in the number of TBI-related hospitalizations and deaths from 2007 to 2013. However, during the same time, the number and rate of older adult fall-related TBIs have increased substantially. Although considerable public interest has focused on sports-related concussion in youth, the findings in this report suggest that TBIs attributable to older adult falls, many of which result in hospitalization and death, should receive public health attention. Public Health Actions The increase in the number of fall-related TBIs in older adults suggests an urgent need to enhance fall-prevention efforts in that population. Multiple effective interventions have been identified, and CDC has developed the STEADI initiative (Stopping Elderly Accidents Deaths and Injuries) as a comprehensive strategy that incorporates empirically supported clinical guidelines and scientifically tested interventions to help primary care providers address their patients’ fall risk through the identification of modifiable risk factors and implementation of effective interventions (e.g., exercise, medication management, and Vitamin D supplementation).
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              The contribution of astrocytes and microglia to traumatic brain injury.

              Traumatic brain injury (TBI) represents a major cause of death and disability in developed countries. Brain injuries are highly heterogeneous and can also trigger other neurological complications, including epilepsy, depression and dementia. The initial injury often leads to the development of secondary sequelae; cellular hyperexcitability, vasogenic and cytotoxic oedema, hypoxia-ischaemia, oxidative stress and inflammation, all of which influence expansion of the primary lesion. It is widely known that inflammatory events in the brain following TBI contribute to the widespread cell death and chronic tissue degeneration. Neuroinflammation is a multifaceted response involving a number of cell types, both within the CNS and in the peripheral circulation. Astrocytes and microglia, cells of the CNS, are considered key players in initiating an inflammatory response after injury. These cells are capable of secreting various cytokines, chemokines and growth factors, and following injury to the CNS, undergo changes in morphology. Ultimately, these changes can influence the local microenvironment and thus determine the extent of damage and subsequent repair. This review will focus on the roles of microglia and astrocytes following TBI, highlighting some of the key processes, pathways and mediators involved in this response. Additionally, both the beneficial and the detrimental aspects of these cellular responses will be examined using evidence from animal models and human post-mortem TBI studies.
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                Author and article information

                Contributors
                janet.alder@rutgers.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                16 November 2020
                16 November 2020
                2020
                : 10
                : 19919
                Affiliations
                [1 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Department of Neuroscience and Cell Biology, , Rutgers Robert Wood Johnson Medical School, ; 683 Hoes Lane West, Research Building 357A, Piscataway, NJ 08854-5635 USA
                [2 ]GRID grid.26009.3d, ISNI 0000 0004 1936 7961, Division of Geriatrics, Department of Medicine, Durham VAMC, GRECC, , Duke University, ; Durham, NC USA
                [3 ]Rutgers Molecular Imaging Center, 41 Gordon Road, Suite D, Room 365A, Piscataway, NJ 08854 USA
                Article
                76849
                10.1038/s41598-020-76849-x
                7670450
                33199792
                20fc5c6b-69e2-47df-96d0-9eac08190e0a
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 June 2020
                : 8 October 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008474, New Jersey Commission on Brain Injury Research;
                Categories
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                © The Author(s) 2020

                Uncategorized
                brain injuries,diseases of the nervous system
                Uncategorized
                brain injuries, diseases of the nervous system

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