Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

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.

TUFM is involved in Alzheimer’s disease‐like pathologies that are associated with ROS

“…The altered TUFM expression in APP/PS1 mice prompted us to test whether TUFM might be involved in AD‐associated pathology. Amyloid‐β precursor protein (APP) that is sequentially cleaved by β‐amyloid converting enzyme 1 (BACE1) and γ‐secretase, leading to the generation of β‐ COOH‐terminal fragment (β‐CTF) and soluble amyloid protein procurer β (sAPPβ) in addition to Aβ 22 . Moreover, A disintegrin and metalloproteinase 10 (ADAM10) are a α‐secretase that facilitates the generation of sAPPα, α‐CTF, and therefore precludes the generation of Aβ 23 .…”

Co-Expression Network Analysis of MicroRNAs and Proteins in Severe Traumatic Brain Injury: A Systematic Review

“…The remaining 88 records were then manually screened and assessed for eligibility against the selection criteria previously described ( Section 2.2 ). Seventy-eight results were excluded during this process, leaving 10 miRNA studies for inclusion in the systematic review [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Figure 1 provides an overview of the miRNA literature search and study selection process.…”

“…The same search filters were applied, leading to 295 results being excluded while a further 71 duplicates were removed using EndNote 20 [ 30 ]. A total of 140 papers were manually excluded following assessment against the selection criteria, leaving a total of 24 papers eligible for inclusion in the review [ 36 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. Figure 2 provides an overview of the protein literature search and study selection process.…”

“…The injury model, time point of analysis post-TBI and analysis method differed across the studies. Supplementary Materials Tables S1 and S2 provide an overview of the study characteristics for the included papers [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. The data collected here allowed us to establish whether performance of a meta-analysis was possible.…”

Blood-Based Brain and Global Biomarker Changes after Combined Hypoxemia and Hemorrhagic Shock in a Rat Model of Penetrating Ballistic-Like Brain Injury

“…15 Several biomarkers are reported to be altered after PBBI, including GFAP (glial fibrillary acidic protein; astrogliosis/astroglial injury), [16][17][18] brain-derived neurotrophic factor (BDNF; neurogenesis/neuroprotection), 19 ubiquitin C-terminal hydrolase-L1 (UCH-L1; neuronal cell body injury), 20 cathepsin B (CatB; apoptosis/ cell necrosis), 21 and microRNA (miRNA; astrogliosis/ inflammation/neurodegeneration). 22,23 Considering that pTBI and polytrauma often occur concurrently in the setting of emergency medicine, we hypothesized that the use of brain-specific and global injury biomarkers can reliably identify HX+HS and frontal PBBI with and without systemic insults (HX+HS) to diagnose and differentiate combined injury from isolated pTBI. The brain-specific biomarkers of interest include the phosphorylated axonal form of the heavy neurofilament subunit (phosphorylated neurofilament-heavy protein [pNF-H]; axonal injury) 15,24,25 and the light neurofilament subunit (neurofilament-light protein [NF-L]; axonal injury).…”