Abstract
Severe traumatic brain injury (TBI) is a risk factor for neurodegenerative diseases. Yet, the molecular events involving dysregulated miRNAs that may be associated with protein degradation in the brain remains elusive. Quantitation of more than 800 miRNAs was conducted using rat ipsilateral coronal brain tissues collected 1, 3, or 7 days after penetrating ballistic-like brain injury (PBBI). As a control for each time-point, Sham-operated animals received craniotomy alone. Microarray and systems biology analysis indicated that the amplitude and complexity of miRNAs affected were greatest 7 day after PBBI. Arrays and Q-PCR inferred that dysregulation of miR-135a, miR-328, miR-29c, and miR-21 were associated with altered levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), PSEN1, PSEN2, and amyloid precursor protein (APP) genes. These events were followed by increased levels of mature BACE1 protein and concomitant loss of full length APP within 3–7 days, then elevation of amyloid beta (Aβ)-40 7 days after PBBI. This study indicates that miRNA arrays, coupled with systems biology, may be used to guide study design prior validation of miRNA dysregulation. Associative analysis of miRNAs, mRNAs, and proteins within a proposed pathway are poised for further validation as biomarkers and therapeutic targets relevant to TBI-induced APP loss and subsequent Aβ peptide generation during neurodegeneration.
Highlights
Severe traumatic brain injury (TBI) remains a significant health issue that leads to cognitive and physical impairment, prolonged hospitalization, and the need for long-term care (Langlois et al, 2005; Zaloshnja et al, 2008; Cuthbert et al, 2015; Taylor et al, 2017)
Patients who suffer from a TBI are at a much higher risk of developing neurodegenerative disease or dementia (Plassman et al, 2000), Alzheimer’s disease (AD) (Mendez et al, 2015), Parkinson’s disease (PD) (Gardner et al, 2018), Amyotrophic lateral sclerosis (ALS) (Franz et al, 2019), psychological disorders (Veitch et al, 2013), post-traumatic stress disorder (PTSD) (FriedemannSanchez et al, 2008), and suicide (Goldstein and Diaz-Arrastia, 2018)
This study showed miR-21 or -214 elevation coupled with miRNA-328 or -135A suppression were associated with beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and PSEN2 modulation, which is in accordance with former studies detailing suppression of BACE1 by miR-135A, miR328, and miR-29c in cell cultures (Zong et al, 2011; Liu et al, 2014b) and transgenic mouse models of AD (Boissonneault et al, 2009)
Summary
Severe traumatic brain injury (TBI) remains a significant health issue that leads to cognitive and physical impairment, prolonged hospitalization, and the need for long-term care (Langlois et al, 2005; Zaloshnja et al, 2008; Cuthbert et al, 2015; Taylor et al, 2017). MiRNAs are implicated in neurodegenerative disorders (Eacker et al, 2009) and linked to increased cell death after brain injury (Truettner et al, 2013). A large number of miRNAs are associated with amyloid precursor protein (APP) degradation and subsequent amyloid beta (Aβ) production (Schonrock et al, 2012), a pathological hallmark of amyloidopathies and neuronal loss (Karnati et al, 2015; He et al, 2018). TBI leads to widespread atrophy that is spurred, in part, by protein degradation, inclusive of full length APP loss and increased levels of Aβ peptides (Purushothuman et al, 2013). It is possible that miRNAs may have a role as key mediators of trauma induced neurodegeneration associated with degradation of full length APP in the brain
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