Neuronal MicroRNA Deregulation in Response to Alzheimer's Disease Amyloid-β

Abstract

Normal brain development and function depends on microRNA (miRNA) networks to fine tune the balance between the transcriptome and proteome of the cell. These small non-coding RNA regulators are highly enriched in brain where they play key roles in neuronal development, plasticity and disease. In neurodegenerative disorders such as Alzheimer's disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, and addresses the hypothesis that amyloid-β (Aβ) itself, a known causative factor of AD, causes neuronal miRNA deregulation, which could contribute to the pathomechanisms of AD. We used sensitive TaqMan low density miRNA arrays (TLDA) on murine primary hippocampal cultures to show that about half of all miRNAs tested were down-regulated in response to Aβ peptides. Time-course assays of neuronal Aβ treatments show that Aβ is in fact a powerful regulator of miRNA levels as the response of certain mature miRNAs is extremely rapid. Bioinformatic analysis predicts that the deregulated miRNAs are likely to affect target genes present in prominent neuronal pathways known to be disrupted in AD. Remarkably, we also found that the miRNA deregulation in hippocampal cultures was paralleled in vivo by a deregulation in the hippocampus of Aβ42-depositing APP23 mice, at the onset of Aβ plaque formation. In addition, the miRNA deregulation in hippocampal cultures and APP23 hippocampus overlaps with those obtained in human AD studies. Taken together, our findings suggest that neuronal miRNA deregulation in response to an insult by Aβ may be an important factor contributing to the cascade of events leading to AD.

Changes in microRNA expression in rat lungs caused by sevoflurane anesthesia: a TaqMan^|^reg; low-density array study

“…To verify the accuracy of our TLDA data, we performed separate standard qRT-PCR experiments for individual miRNAs using single Taqman microRNA assays (Applied Biosystems) (28). Single TaqMan assays rely on the same technology as TLDA.…”

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

“…Several recent works revealed that relevant miRNAs altered Ab expression (Hebert et al, 2008;Hebert et al, 2009;Schonrock et al, 2010;Vilardo et al, 2010). miRNAs might alter the proteins expression, contributing to the pathogenesis of neurodegenerative disease of the accumulation of toxic proteins (Eacker et al, 2009).…”

“…miRNA dysfunction could be both a cause and a consequence of this neurodegenerative disease. Using sensitive TaqMan low density miRNA arrays and bioinformatic analysis, the Ab was found to cause neuronal miRNA deregulation, whereas neuronal miRNA network deregulation could significantly contribute to the cascade of events leading to AD (Schonrock et al, 2010).…”

Advances in MicroRNAs and Alzheimer’s Disease Research

“…However, while the miR-328 sequence is perfectly conserved between mouse and human, that of miR-298 is only 72% identical. More recently the hypothesis that A itself causes neuronal miRNA deregulation which could contribute to the pathology associated with AD was explored (Schonrock et al 2010). A list of miRNAs, miR-9, miR-181c, miR-30c, miR-20b, miR-148b and Let-7i, was also downregulated in primary hippocampal cell cultures treated with A.…”