Abstract
Traumatic brain injury (TBI) survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in many severe TBI patients, results in accumulation of amyloid precursor protein (APP). Post-injury enzymatic cleavage of APP can generate amyloid-β (Aβ) peptides, a hallmark finding in Alzheimer’s disease (AD). At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Aβ peptides and tau may be used as biomarkers in interstitial fluid (ISF) using cerebral microdialysis and/or cerebrospinal fluid (CSF) following clinical TBI. In the present review, the available clinical and experimental literature on Aβ peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Aβ peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Aβ peptides may be neurotoxic. Increased CSF and/or ISF Aβ levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques, and the complexity of TBI in the available studies make the clinical value of tau and Aβ as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Aβ peptides and the future risk of developing AD remains unclear. Future studies using methods such as rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Aβ peptides and tau protein in both the acute pathophysiology and long-term consequences of TBI.
Highlights
In the United States, around 1.4 million people sustain a traumatic brain injury (TBI) annually (Zohar et al, 2011; Sivanandam and Thakur, 2012) and younger individuals are predominately affected (Fins, 2003; Kovesdi et al, 2010)
We focus on the available evidence for increased Aβ and tau pathology in injured brain tissue and the use of Aβ peptides and tau as potential biomarkers in the cerebrospinal fluid (CSF) and interstitial fluid (ISF) following TBI
Available experimental and clinical evidence implies a complex relationship between increased tau protein release, Aβ peptide deposition, and neurofibrillary tangles (NFTs) and Aβ plaque formation following TBI
Summary
In the United States, around 1.4 million people sustain a traumatic brain injury (TBI) annually (Zohar et al, 2011; Sivanandam and Thakur, 2012) and younger individuals are predominately affected (Fins, 2003; Kovesdi et al, 2010). The pathophysiology of TBI is complex and involves multiple cellular and biochemical changes generated by the initial impact, leading to a disease process which exacerbate the injury for a prolonged period of time. This secondary injury process involves inflammatory cascades and heterogenous cell death pathways including apoptosis, autophagia, and necrosis (Kovesdi et al, 2007; Loane et al, 2009; Marklund and Hillered, 2011; Sivanandam and Thakur, 2012). Elevated APP levels in injured axons may be due to a combination of increased neuronal expression and accumulation due to www.frontiersin.org
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