Alzheimer's Disease (AD) is an age-associated neurodegenerative disorder that progressively
and irreversibly yields a loss of cognitive function (Masters et al., 2015). Among
the multiple theories rooting for the cause of AD, prominent and widely studied ones
are the accumulation of amyloid-beta protein and neurofibrillary tangles that disturb
cellular and synaptic transmission (Wang et al., 2014; Gouras et al., 2015). Other
less-studied theories cite the role of oxidative stress, neuroinflammation, metabolism
imbalance, and autophagy-related mechanisms in AD progression (Xu et al., 2015). Despite
the decades of developing treatments, current medication is partly successful in easing
some AD symptoms. Given the multifactorial nature of AD progression, presently, no
treatment is available that could either inhibit or limit the progressive decline.
Non-coding RNA (ncRNA) mechanisms in AD recently attracted a lot of attention (Tan
et al., 2013). Besides the abundant transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs),
recently long (lncRNAs) and small ncRNAs viz. microRNAs, competing for endogenous
RNAs (ceRNAs), circular RNAs (circRNA), exosome miRNAs (ex-miRNAs), and Piwi-interacting
RNA (piRNA) has been at the center of discussion in AD pathology (Doxtater et al.,
2020). Single ncRNA can regulate the expression of many genes across the CNS, implying
if ncRNA function is dysregulated, it may trigger multiple pathogenic pathways in
the brain (Vijayan and Reddy, 2020). Anticipatedly, multiple recent studies have confirmed
dysregulated expression of ncRNA's in AD (Millan, 2017). As ncRNA analysis is quicker
and cost-effective, its utility in diagnosis may help discriminate between different
forms of neurodegenerative disease (Lauretti et al., 2021). Although, recent research
on ncRNAs opens a new dimension of knowledge on the mechanisms of AD pathology, there
is still much to explore.
In this context, the original research articles and mini/systematic reviews published
in the present Research Topic shed light on the role of ncRNAs in AD pathology and
provide a larger understanding of the ncRNA mechanisms in AD and their utility for
diagnostics and therapeutics.
In an insightful report, Huaying et al. obtained 3,158 lncRNAs by microarray data
re-annotation and developed a global network of competing endogenous RNAs (ceRNAs)
for AD and normal samples based on their transcriptional profiles. By correlating
gene expression data, they identified a total of 255 AD-deficient messenger RNA (mRNA)-lncRNAs.
A majority of dysregulated ceRNAs genes were enriched in transcription factors and
miRNAs, while the identified miRNA in the lncRNA-mRNA network showed that 40 lncRNA
pairs share more than one identified miRNA. Of note, nine lncRNAs were found to be
associated with AD, PD, and other neurodegenerative pathologies. More specifically,
five lncRNAs were identified to be potential biomarkers for AD. Further, they identified
a relative decline in PART1 and an increase in SNHG14 transcript levels in the AD
serum samples. Conclusively, they elucidated the role of lncRNAs in the pathogenesis
of AD and also the potential utility of new lncRNAs in the diagnostics and therapeutics
of AD.
Weighing on the emerging significance of lncRNAs in AD, Asadi et al. in a systematic
review, evaluated the association between lncRNAs and AD. Dysregulated functions of
lncRNAs in the diverse regulatory pathways in CNS are suspected to play a role in
AD pathology that is mainly characterized by the formation of amyloid plaques with
the accumulation of β-amyloid and neurofibrillary tangles (NFT) that form as a result
of the phosphorylated tau accumulation. To examine this association of lncRNAs in
AD, they adopted a six-step strategy and systematically surveyed the published research
across seven databases as per the Prisma guideline. Of the 1,591 research reports,
69 articles met the specified inclusion criteria of the original research on AD performed
by established molecular techniques. The majority of these reports highlighted the
role of BACE1-AS, MALAT1, NEAT1, and SNHG1 lncRNAs in AD, whereas nearly one-third
of the reports researched a unique lncRNA. Of note, nearly 56 and 7% of the investigations
reported an increase and decline in the lncRNAs levels, respectively. In the line,
another review by Zhang et al. comprehensively shed light on the ncRNAs implications
in AD and the role of key regulatory pathways in discovering the novel druggable targets
in AD. Weighing on ncRNAs therapeutic potential as seen in the preclinical stages
of AD (as the earliest feasible druggable targets), they stressed the applications
of mimicking or inhibitory ncRNAs in regulating their downstream target mRNAs as interventional
therapeutics for AD. The review also highlighted the use of miRNAs and Piwi-interacting
RNA (piRNA) as key drug targets for therapeutics in murine models of AD. They underlined
the application of circRNAs and lncRNAs with MREs function to work like miRNA sponges
that could influence the mRNA-regulating activities of miRNAs. They anticipated a
future focus on sensitive RNA detection assays to ascertain the utility of key ncRNAs
for preclinical or diagnostic applications for AD.
The function of circRNAs, a novel type of endogenous ncRNA is implicated in regulating
gene expression in mammals. Recent studies revealed the relevance of circRNAs with
neurological diseases, including AD. To gain further insight into it, in original
research, Liu et al. identified an aberrant circRNA, viz. hsa_circ_0003391, that exhibited
a significant downregulation in the peripheral blood of AD patients. To evaluate the
clinical manifestation of hsa_circ_0003391 in AD, a receiver operating characteristic
(ROC) curve analysis was performed to assess its potential diagnostic value, which
was found to be statistically significant [area under the curve (AUC) value: 0.7283].
Bioinformatics approaches further predicted miR-574-5p to be a potential hsa_circ_0003391
target, which exhibited an anticipated increase in the AD groups. These results hinted
at a potential correlation of hsa_circ_0003391 expression with clinical manifestations
of AD. Overall, this report suggested a potential relationship of decreased hsa_circ_0003391
levels in the peripheral blood with AD and hinted at the development of novel AD therapeutics
by targeting ncRNA. In this line, a mini review by Dong et al. assessed research on
exosome miRNAs (ex-miRNAs) that function in clinical dementia and examined the potency
of ex-miRNAs as an early diagnostic biomarker for common or AD-related dementia. They
highlighted the necessity of a reliable biomarker for the cerebrospinal fluid (CSF)
and peripheral blood that may enable early clinical diagnosis of dementia. Given the
susceptibility of interference by several factors in the peripheral circulation to
circulating miRNA, they argued the suitability of ex-miRNAs for diagnosis, citing
their greater stability.
In another comprehensive review report, Samadian et al. conferred recent evidence
emphasizing the role of miRNAs in the development of AD. The review carefully assessed
the role of several miRNAs, viz. miR-195, miR-200a-3p, miR-338-5p, miR-125b-5p, miR-34a-5p,
miR-132, miR-339-5p, miR-384, miR-425-5p, miR-135b, and miR-339-5p, those were shown
to have a function in the development of AD through their interaction with BACE1.
Several other miRNAs were suggested to impact the inflammatory responses in AD progression.
This review amply covers new knowledge on the aberrant expression of miRNAs in the
plasma of AD subjects, aptitude for differentiation, and AD-modifying agents that
affect miRNA profiles in vitro or in vivo models.
In conclusion, this Research Topic collects evidence highlighting the relevance of
ncRNAs in AD pathology and its progression. It specifically conferred the diverse
role that lncRNAs, microRNAs, ceRNAs, circRNA, ex-miRNAs, piRNA play in AD pathology
and may also pave the way for its diagnosis and therapeutics in clinics.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution
to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.
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