molecules Review RNA Dynamics in Alzheimer’s Disease Agnieszka Rybak-Wolf 1,* and Mireya Plass 2,3,4,* 1 Max Delbrück Center for Molecular Medicine (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany 2 Gene Regulation of Cell Identity, Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain 3 Program for Advancing Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet del Llobregat, 08908 Barcelona, Spain 4 Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain * Correspondence: [email protected] (A.R.-W.); [email protected] (M.P.) Abstract: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance Citation: Rybak-Wolf, A.; Plass, M. of specific RNA species are linked to the pathology of AD. RNA Dynamics in Alzheimer’s Disease. Molecules 2021, 26, 5113. Keywords: Alzheimer’s disease; neurodegenerative diseases; RNA binding proteins; RNA process- https://doi.org/10.3390/ ing; post-transcriptional regulation; alternative splicing; miRNAs; circRNAs; lncRNAs molecules26175113 Academic Editors: Inmaculada Segura and Sandra 1. Introduction M. Fernandez-Moya Alzheimer’s disease (AD) is the most common type of age-related dementia for which no cure is yet available. Currently, it is estimated that 10–30% of the population older than Received: 16 July 2021 65 years has AD [1], from which only about 1–5% of the cases have clearly known genetic Accepted: 17 August 2021 Published: 24 August 2021 causes [2]. One of the main characteristics of AD is that it is a slowly progressing neurodegenera- tive disease. It has been shown that AD-associated intraneural lesions can occur in young Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in individuals [3,4] several decades before the appearance of cognitive symptoms, which is published maps and institutional affil- known as the preclinical phase of AD [5]. This phase is later followed by the appearance iations. of cognitive symptoms that begin with mild memory loss that gradually turns towards a severe impairment of executive and cognitive functions over the course of one or two decades [6]. At the molecular level, AD is characterized by the accumulation of amyloid β (Aβ) peptides in plaques and the presence of phosphorylated Tau aggregates in neurofibrillary Copyright: © 2021 by the authors. tangles (NFT) [7]. For decades, it was thought that AD-related cognitive impairments Licensee MDPI, Basel, Switzerland. β This article is an open access article were caused by the accumulation of a A peptides in the brain parenchyma. The so- distributed under the terms and called amyloid hypothesis suggested that the formation of amyloid plaques that lead to conditions of the Creative Commons neuronal degeneration and death was the cause of AD [8]. This hypothesis has been the Attribution (CC BY) license (https:// lead target for drug development to treat AD. However, clinical trials targeting Aβ remain creativecommons.org/licenses/by/ unsuccessful in improving cognitive function or slowing down disease progression [9]. 4.0/). Molecules 2021, 26, 5113. https://doi.org/10.3390/molecules26175113 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 25 Molecules 2021, 26, 5113 2 of 24 cessful in improving cognitive function or slowing down disease progression [9]. There- fore, these results suggest that the accumulation of Aβ peptides, as posed in the amyloid Therefore, these results suggest that the accumulation of Aβ peptides, as posed in the hypothesis, cannot itself explain the onset and progression of AD. amyloid hypothesis, cannot itself explain the onset and progression of AD. Recently, a new focus has been placed on the role of RNA processing and its impact Recently, a new focus has been placed on the role of RNA processing and its impact on neurodegenerative diseases. RNA binding proteins (RBPs) are the main regulators of on neurodegenerative diseases. RNA binding proteins (RBPs) are the main regulators gene regulation at the RNA level, including transcription, processing, transport, and deg- of gene regulation at the RNA level, including transcription, processing, transport, and radation. In this review, we will summarize the current evidence showing how RBP ex- degradation. In this review, we will summarize the current evidence showing how RBP pression and function are altered in AD and how these changes affect the biogenesis, ex- expression and function are altered in AD and how these changes affect the biogenesis, pression, processing, and localization of coding and non-coding RNAs (ncRNAs) in AD, expression, processing, and localization of coding and non-coding RNAs (ncRNAs) in AD, asas wellwell asas theirtheir impactimpact onon ADAD pathology.pathology. 2.2. RNA ProcessingProcessing GovernsGoverns thethe RNARNA MakeupMakeup ofof CellsCells WithinWithin anan organism,organism, eacheach cellcell expressesexpresses a different combination of genes that consti- tutestutes itsits uniqueunique fingerprint.fingerprint. ThisThis fingerprint,fingerprint, knownknown asas thethe transcriptome,transcriptome, reflectsreflects severalseveral aspectsaspects of thethe cell,cell, allowingallowing us to identify, amongamong others,others, itsits function,function, itsits activationactivation state,state, andand eveneven itsits responseresponse toto thethe surroundingsurrounding environmentenvironment [10[10––1212]].. SeveralSeveral interconnectedinterconnected mechanismsmechanisms and processes processes are are involved involved in in controlling controlling the the specific specific RNA RNA makeup makeup of a ofcell, a cell,including including transcription, transcription, splicing, splicing, polyadenylation, polyadenylation, nuclear nuclear export, transport, export, transport, and turnover and turnover[13]. Apart [13 from]. Apart transcription, from transcription, which requires which requires the recognition the recognition of specific of specific signals signals in the inDNA, the DNA,all mechanisms all mechanisms that regulate that regulate gene geneexpression expression post- post-transcriptionallytranscriptionally are largely are largely reg- regulatedulated by byRNA RNA binding binding proteins proteins (RBPs). (RBPs). RBPsRBPs are are proteins proteins that that bind bind to RNA to RNA and regulate and regulate their fate their and functionfate and post-transcriptionally function post-tran-. RBPsscriptionally. function RBPs both function in the nucleus both in the and nucleus the cytoplasm, and the cytoplasm, although their although specific their roles specific are compartmentroles are compartment dependent. dependent. In the nucleus, In the RBPs nucleus, mainly RBPs regulate mainly RNA regulate processing, RNA processing, including splicing,including polyadenylation, splicing, polyadenylation, and export. and In export. the cytoplasm, In the cytoplasm, RBPs regulate RBPs RNA regulate silencing, RNA degradation,silencing, degradation, transport, tr andansport translation,, and translation as well, asas bothwell as protein both protein and RNA and localization RNA local- (Figureization1 (Figure). 1). FigureFigure 1.1.RNA RNA processing processing in in AD. AD. Schematic Schematic representation representation of theof the main main processes processes regulated regulated by RBPs by RBPs and RNAsand RNAs within within cells andcells their and alterationstheir alterations in AD. in The AD. figure The figure depicts depicts the biogenesis the biogenesis of the mainof the coding main coding and non-coding and non-coding RNA species, RNA species, including in- cluding mRNAs, lncRNAs, miRNAs, and circRNAs, as well as the main RNA regulatory processes, including transcrip- mRNAs, lncRNAs, miRNAs, and circRNAs, as well as the main RNA regulatory processes, including transcription, splicing, tion, splicing, RNA transport, storage, translation, and RNA degradation. Additionally, we highlight some of the known RNA transport, storage, translation, and RNA degradation. Additionally, we highlight some of the known RNA processing RNA processing alterations described in AD, including (1) changes in the expression of mRNA isoforms of AD-related alterationsgenes (blue); described (2) RBPs in with AD, includingaltered function (1) changes (grey); in theand expression (3) miRNA of and mRNA lncRNA isoforms with of altered AD-related expression genes (blue);(black). (2) Genes, RBPs withRNAs, altered and RBPs function appear (grey); next and to the (3) miRNArelevant and biological lncRNA process