Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer's disease: An integrative review

Abstract

The human genome encodes a vast repertoire of protein non-coding RNAs (ncRNA), some specific to the brain. MicroRNAs, which interfere with the translation of target mRNAs, are of particular interest since their deregulation has been implicated in neurodegenerative disorders like Alzheimer's disease (AD). However, it remains challenging to link the complex body of observations on miRNAs and AD into a coherent framework. Using extensive graphical support, this article discusses how a diverse panoply of miRNAs convergently and divergently impact (and are impacted by) core pathophysiological processes underlying AD: neuroinflammation and oxidative stress; aberrant generation of β-amyloid-42 (Aβ42); anomalies in the production, cleavage and post-translational marking of Tau; impaired clearance of Aβ42 and Tau; perturbation of axonal organisation; disruption of synaptic plasticity; endoplasmic reticulum stress and the unfolded protein response; mitochondrial dysfunction; aberrant induction of cell cycle re-entry; and apoptotic loss of neurons. Intriguingly, some classes of miRNA provoke these cellular anomalies, whereas others act in a counter-regulatory, protective mode. Moreover, changes in levels of certain species of miRNA are a consequence of the above-mentioned anomalies. In addition to miRNAs, circular RNAs, piRNAs, long non-coding RNAs and other types of ncRNA are being increasingly implicated in AD. Overall, a complex mesh of deregulated and multi-tasking ncRNAs reciprocally interacts with core pathophysiological mechanisms underlying AD. Alterations in ncRNAs can be detected in CSF and the circulation as well as the brain and are showing promise as biomarkers, with the ultimate goal clinical exploitation as targets for novel modes of symptomatic and course-altering therapy.

Keywords: Apoptosis; Autophagy; Cell cycle re-entry; Circular RNA; Endoplasmic reticulum; Epigenetic; Long non-coding RNA; MicroRNA; Neurodegenerative; Neuroinflammation; Non-coding RNA; Oxidative stress; Secretase; Tau; Unfolded protein response; lncRNA; miR; ncRNA; piRNA; β-amyloid.