microRNA-Based Biomarkers in Alzheimer’s Disease (AD)

Abstract

Alzheimer's disease (AD) is a multifactorial, age-related neurological disease characterized by complex pathophysiological dynamics taking place at multiple biological levels, including molecular, genetic, epigenetic, cellular and large-scale brain networks. These alterations account for multiple pathophysiological mechanisms such as brain protein accumulation, neuroinflammatory/neuro-immune processes, synaptic dysfunction, and neurodegeneration that eventually lead to cognitive and behavioral decline. Alterations in microRNA (miRNA) signaling have been implicated in the epigenetics and molecular genetics of all neurobiological processes associated with AD pathophysiology. These changes encompass altered miRNA abundance, speciation and complexity in anatomical regions of the CNS targeted by the disease, including modified miRNA expression patterns in brain tissues, the systemic circulation, the extracellular fluid (ECF) and the cerebrospinal fluid (CSF). miRNAs have been investigated as candidate biomarkers for AD diagnosis, disease prediction, prognosis and therapeutic purposes because of their involvement in multiple brain signaling pathways in both health and disease. In this review we will: (i) highlight the significantly heterogeneous nature of miRNA expression and complexity in AD tissues and biofluids; (ii) address how information may be extracted from these data to be used as a diagnostic, prognostic and/or screening tools across the entire continuum of AD, from the preclinical stage, through the prodromal, i.e., mild cognitive impairment (MCI) phase all the way to clinically overt dementia; and (iii) consider how specific miRNA expression patterns could be categorized using miRNA reporters that span AD pathophysiological initiation and disease progression.

Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression

“…Progressive, low-grade, systemic inflammation and inflammatory neurodegeneration is known to be linked with a complicated network of miRNAs and their target mRNAs, out of which some miRNAs play a promoting role [ 49 ]. In contrast, the miR-483-5p activity reported here seems to represent neuroprotective/compensatory mechanisms in AD.…”

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

“…In similar studies analyzing the influence of the confounding factors age and sex on miRNA profiles from peripheral blood, it was found that very few single miR-NAs remained significantly associated with age and sex after adjustment using multiple testing parameters 44 . This lack of significant association may also be a reflection of (I) the observation that many miRNA biomarkers show discrepant results in independent investigations of the same disease, and (II) the remarkable heterogeneity of miRNA complexity and expression patterns in neurological disorders, such as those observed across the entire AD continuum 45 . We report significantly lower levels of miRNA-15b in Aβ-positive individuals than -negative ones.…”

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

“…The miR-34 and miR-122 miRNAs have been used in the treatment of certain types of cancer and hepatitis, with promising results [ 64 ]. On the other hand, some miRNAs (miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155) may be involved in the physiopathology of AD, and some act on the Wnt/β-catenin pathway [ 65 ], which is involved in both neurodegenerative diseases and tumors. A recent paper suggested a potential anti-β-amyloid protective effect of miRNA-15b and a biological link between miRNA-125b and neurotoxic pathways, hypothesizing that these miRNAs may play a role as biomarkers of AD physiopathology with therapeutic potential [ 66 ].…”