Abstract
ABSTRACT The blood-brain barrier (BBB) plays a pivotal role in the maintenance and regulation of the neural microenvironment. The BBB breakdown is a pathological change in early Alzheimer’s disease (AD). RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are involved in the regulation of BBB permeability. Our study demonstrates the role of TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of the BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased BBB permeability due to increased expression of tight junction-related proteins. ELK4 was less expressed in the BBB model in AD microenvironment in vitro. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. Downregulation of ELK4 increased BBB permeability by increasing the tight junction-related protein expression.TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.
Highlights
Alzheimer’s disease (AD), as the most common cause of dementia, seriously affects human health and quality of life[1]
3.1 TRA2A was highly expressed in Aβ1–42-incubated endothelial cells (ECs), and knockdown of TRA2A attenuatd blood-brain barrier (BBB) permeability in AD microenvironment
We focused on the three proteins to investigate the mechanism of action of TRA2A on BBB permeability
Summary
Alzheimer’s disease (AD), as the most common cause of dementia, seriously affects human health and quality of life[1]. The occurrence of blood-brain barrier (BBB) disruption is the pathological change of early AD. The increase of BBB permeability aggravates the degeneration of blood vessels and neurons[3, 4]. Function changes of BBB in AD have been a great challenge for identification of pathogenesis and treatments[5]. BBB is composed of cerebral microvascular endothelial cells (ECs), pericytes, extracellular matrix and podocytes of perivascular astrocytes[6]. The tight junctions between adjacent ECs play a critical role in maintaining BBB integrity. It has been reported that BBB disruption in AD mainly reduces Aβ clearance[4], allowing influx into the brain of neurotoxic blood-derived debris, cells, and microbial pathogens, and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration[7]
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