A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer’s Disease and Mild Cognitive Impairment from Healthy Controls

Abstract

The most frequently used biomarkers to support the diagnosis of Alzheimer’s Disease (AD) are Aβ42, total-Tau, and phospho-tau protein levels in CSF. Moreover, magnetic resonance imaging is used to assess hippocampal atrophy, 18F-FDG PET to identify abnormal brain metabolism, and PET imaging for amyloid deposition. These tests are rather complex and invasive and not easily applicable to clinical practice. Circulating non-coding RNAs, which are inherently stable and easy to manage, have been reported as promising biomarkers for central nervous system conditions. Recently, circular RNAs (circRNAs) as a novel class of ncRNAs have gained attention. We carried out a pilot study on five participants with AD and five healthy controls (HC) investigating circRNAs by Arraystar Human Circular RNA Microarray V2.0. Among them, 26 circRNAs were differentially expressed (FC ≥ 1.5, p < 0.05) in participants with AD compared to HC. From a top 10 of differentially expressed circRNAs, a validation study was carried out on four up-regulated (hsa_circRNA_050263, hsa_circRNA_403959, hsa_circRNA_003022, hsa_circRNA_100837) and two down-regulated (hsa_circRNA_102049, hsa_circRNA_102619) circRNAs in a larger population. Moreover, five subjects with mild cognitive impairment (MCI) were investigated. The analysis confirmed the upregulation of hsa_circRNA_050263, hsa_circRNA_403959, and hsa_circRNA_003022 both in subjects with AD and in MCI compared to HCs. We also investigated all microRNAs potentially interacting with the studied circRNAs. The GO enrichment analysis shows they are involved in the development of the nervous system, and in the cellular response to nerve growth factor stimuli, protein phosphorylation, apoptotic processes, and inflammation pathways, all of which are processes related to the pathology of AD.

Prenatal alcohol exposure dysregulates spinal and circulating immune cell circular RNA expression in adult female rats with chronic sciatic neuropathy

“…Interpretation of whether or how circVopp1 regulates linear Vopp1 levels is limited at this point, our data suggest that dysregulated circ-and linear Vopp1 levels may contribute to aberrant NF-κB signaling affecting immune function in PAE offspring. Moreover, peripheral blood-identified circRNAs may serve as potential biomarkers for CNS pathologies (Lu and Xu, 2016;Liu et al, 2020;Piscopo et al, 2022), often an indicator of disease prognosis (Gaffo et al, 2019;Ravanidis et al, 2021). Although opposite to what was observed in blood, our real-time PCR data suggesting the altered circVopp1 levels in both the periphery and CNS tissue may identify circVopp1 as an ideal marker of PAE-related CNS dysfunction.…”

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

“…For instance, Song et al [ 14 ] reported that circCwc27 interacts with purine-rich element-binding protein A (Pur-α), halts nuclear transport of Pur-α, reduces Pur-α binding to the promoter of amyloid precursor protein (APP), and leads to Aβ deposition and memory impairment in 6-month-old APP/PS1 mice. Moreover, blood circRNAs have been reported as promising biomarkers for AD diagnosis [ 15 , 16 ]. However, the direct link between circRNA dysregulation and synaptic impairment in the early stage of AD is not clear.…”

Non-Coding RNA in Microglia Activation and Neuroinflammation in Alzheimer’s Disease

“…Although further studies are required to fully characterize the expression profiles and functions of circulating circRNAs, these findings suggest that circRNAs hold promise as novel biomarkers for both preclinical and clinical stages of AD. 221 …”