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      The brain’s weakness in the face of trauma: How head trauma causes the destruction of the brain

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          Abstract

          Of all our organs, the brain is perhaps the best protected from trauma. The skull has evolved to enclose it and, within the skull, the brain floats in a protective bath of cerebrospinal fluid. It is becoming evident, however, that head trauma experienced in young adult life can cause a dementia that appears decades later. The level of trauma that induces such destruction is still being assessed but includes levels well below that which cracks the skull or causes unconsciousness or concussion. Clinically this damage appears as dementia, in people who played body-contact sports in their youth or have survived accidents or the blasts of combat; and appears also, we argue, in old age, without a history of head trauma. The dementias have been given different names, including dementia pugilistica (affecting boxers), chronic traumatic encephalopathy (following certain sports, particularly football), traumatic brain injury (following accidents, combat) and Alzheimer’s (following decades of life). They share common features of clinical presentation and neuropathology, and this conceptual analysis seeks to identify features common to these forms of brain injury and to identify where in the brain the damage common to them occurs; and how it occurs, despite the protection provided by the skull and cerebrospinal fluid. The analysis suggests that the brain’s weak point in the face of trauma is its capillary bed, which is torn by the shock of trauma. This identification in turn allows discussion of ways of delaying, avoiding and even treating these trauma-induced degenerations.

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          Most cited references63

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          The pathobiology of vascular dementia.

          Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

            Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE).
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              Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.

              Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                02 March 2023
                2023
                : 17
                : 1141568
                Affiliations
                [1] 1School of Biomedical Sciences and Pharmacy, University of Newcastle and School of Medical Sciences, The University of Sydney , Darlington, NSW, Australia
                [2] 2Fonds de Dotation Clinatec, Université Grenoble Alpes, France and Institute of Ophthalmology, University College London , London, United Kingdom
                [3] 3Honorary Associate, Centenary Institute and University of Sydney , Darlington, NSW, Australia
                Author notes

                Edited by: Einar M. Sigurdsson, New York University, United States

                Reviewed by: Alexei Verkhratsky, The University of Manchester, United Kingdom; Juliet Haarbauer Krupa, Centers for Disease Control and Prevention (CDC), United States

                *Correspondence: Jonathan Stone, jonathanston@ 123456gmail.com

                This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2023.1141568
                10026135
                36950132
                8e4b1cc0-b911-4bbd-a09d-174aa88e5594
                Copyright © 2023 Johnstone, Mitrofanis and Stone.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 January 2023
                : 15 February 2023
                Page count
                Figures: 2, Tables: 0, Equations: 1, References: 66, Pages: 11, Words: 9515
                Categories
                Neuroscience
                Review

                Neurosciences
                neurodegeneration,head trauma,concussion,alzheimer’s,cte,dementia pugilistica
                Neurosciences
                neurodegeneration, head trauma, concussion, alzheimer’s, cte, dementia pugilistica

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