Amyloid-β Peptides and Tau Protein as Biomarkers in Cerebrospinal and Interstitial Fluid Following Traumatic Brain Injury: A Review of Experimental and Clinical Studies

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.

<em>In Vitro</em> Aggregation Assays Using Hyperphosphorylated Tau Protein

“…For example, there are reports that the neurofibrillary tangles are detectable in some patients of chronic traumatic encephalopathy, such as professional American football players and boxers [50][51][52] . Similar correlation has also been reported for single or repetitive traumatic brain injury patients including soldiers 53 . Protocols described in this work may thus help the discovery and development of new therapeutics targeting p-tau aggregates in neuronal cells.…”

Traumatic brain injury as a risk factor for Alzheimer's disease: current knowledge and future directions

“…However, studies of Aβ peptide levels in humans with TBI have produced contradictory results [20,21]. Additional research has demonstrated increased levels of hyperphosphorylated tau protein, the same protein involved in the NFTs in AD, are found in individuals who have experienced a severe TBI [22]; however, it remains unclear whether or how TBI-associated plaques identified acutely after injury develop into the dense neuritic plaques that are the hallmark pathological features of AD.…”

“…Pathological data gathered from individuals who survive more than a year after moderate-severe TBI increasingly suggest that post-TBI neurodegeneration is best described as a polypathology [64]; in other words, multiple distinct pathological processes may underlie and contribute to the late-life neurodegeneration experienced by some TBI survivors. As discussed above, research has also demonstrated increased levels of hyperphosphorylated tau protein after severe TBI [22,65], hypoxia-related changes in gene expression [66], injury-related vascular damage [67], chronically upregulated systemic inflammatory markers [68,69] and other potentially relevant processes [70], each of which can contribute to distinct neurodegenerative pathological processes that may evolve over time after TBI. Indeed, the largest study to date on latelife TBI outcomes was published in July 2016; this study pooled data from 7130 adults over the age of 65 years who were alive and dementiafree at the time of entry into prospective longitudinal cohort studies to evaluate associations between TBI and late-life clinical dementia outcomes and neuropathological findings for those with autopsy data [71].…”

Current Therapeutic Modalities, Enzyme Kinetics, and Redox Proteomics in Traumatic Brain Injury

“…Cleavage of amyloid precursor protein (APP), which produces amyloid-β (Aβ) peptide, is a common hallmark in AD. At autopsy, TBI patients have reported Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins, thus leading to the hypothesis that AD can possibly be a secondary effect of TBI [25]. A past study showed that an increase of neuronal C5a receptors and C5b-9 terminal complex, a promoter of the cell cycle and cell lysis, in diffuse axonal injury (DAI) of TBI, could lead to possible secondary neuronal cell death [26,27].…”