Abstract
MicroRNAs (miRNAs) have emerged as critical regulators in the pathology of Alzheimer’s disease (AD). MiR-181a is associated with hippocampal memory formation and aberrantly expressed in patients with mild cognitive impairment (MCI), however, little is known about its role and underlying mechanism involved in AD. Here, we report that miR-181a expression declines in APP/PS1 mice, synchronous with the increase in amyloid β (Aβ) level, which suggests a reverse correlation between miR-181a level and AD development. Additionally, lentiviral overexpression of miR-181a via intrahippocampal injection ameliorates cognitive deficits and amyloid plaque deposition in APP/PS1 mice, indicating a beneficial role of miR-181a against AD progression. Moreover, miR-181a decelerates pericyte loss and blood-brain barrier breakdown in APP/PS1 mice. Furthermore, miR-181a protects against Aβ accumulation-induced pericyte apoptosis in vitro, which is attributed to the negative regulation of FOXO1 by miR-181a, since FOXO1 restoration abolishes miR-181a protective role against pericyte apoptosis. Altogether, these results may identify miR-181a as a novel regulator of AD pathology, and also implicate that the protection of miR-181a in blood-brain barrier pericytes may underlie its ameliorating effect on APP/PS1 mice.
Highlights
Pericytes are a type of vascular mural cells typically localized in the basement membrane of blood microvessels [1]
In the central nervous system (CNS), pericytes are distributed in the blood-brain barrier (BBB), where they are centrally positioned in the neurovascular unit (NVU), which is comprised of endothelial cells, astrocytes and neurons [2]
Pericyte degeneration and BBB breakdown have been found in www.aging-us.com some neurological disorders, such as spinal cord injury [6], including Alzheimer’s disease (AD) [7, 8], a neurodegenerative disease characterized by abnormally elevated amyloid β-peptide (Aβ), tau pathology and neuronal loss, which lead to progressive cognitive decline, and dementia [9, 10]
Summary
Pericytes are a type of vascular mural cells typically localized in the basement membrane of blood microvessels [1]. Through taking advantage of transgenic APP/PS1 mice, a murine AD model, we show an ameliorating effect of miR-181a on cognitive deficits, which may relate to the retarded pericyte loss and blood-brain barrier breakdown via a negative regulation of pericyte apoptosis.
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