Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Urdánoz‐Casado, Amaya; Gordoa, Javier Sánchez‐Ruiz de; Robles, Maitane; Roldán, Miren; Zelaya, María Victoria; Blanco‐Luquin, Idoia; Mendioroz, Maite

doi:10.3390/ijms23147682

Cited by 7 publications

(6 citation statements)

References 82 publications

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“…It is noteworthy, although not surprising, that among the worst candidates we can find genes, such as GAPDH and ACTB, which are routinely employed as reference genes for normalizing expression data of target genes in all the different samples or experimental conditions, without further validation. Gene expression studies with human HMC3 microglia line are no exception; for example some of the most recent ones report analyses with only one reference gene, such as GAPDH 18,[20][21][22] , ACTB 31,59,60 or a combination of the two 61 . We only identified one gene expression study with normalized data using B2M and HPRT1 62 .…”

Section: Discussionmentioning

confidence: 99%

Selection of suitable reference genes for gene expression studies in HMC3 cell line by quantitative real-time RT-PCR

Fazzina,

Bergonzoni,

Massenzio

et al. 2024

Sci Rep

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Microglia represent the primary immune defense system within the central nervous system and play a role in the inflammatory processes occurring in numerous disorders, such as Parkinson’s disease (PD). PD onset and progression are associated with factors considered possible causes of neuroinflammation, i.e. genetic mutations. In vitro models of microglial cells were established to identify specific molecular targets in PD through the analysis of gene expression data. Recently, the Human Microglial Clone 3 cell line (HMC3) has been characterized and a new human microglia model has emerged. Here we perform RT-qPCR analyses to evaluate the expression of ten reference genes in HMC3, untreated or stimulated to a pro-inflammatory status. The comparative ∆CT method, BestKeeper, Normfinder, geNorm and RefFinder algorithms were used to assess the stability of the candidate genes. The results showed that the most suitable internal controls are HPRT1, RPS18 and B2M genes. In addition, the most stable and unstable reference genes were used to normalize the expression of a gene of interest in HMC3, resulting in a difference in the statistical significance in cells treated with Rotenone. This is the first reference gene validation study in HMC3 cell line in pro-inflammatory status and can contribute to more reliable gene expression analysis in the field of neurodegenerative and neuroinflammatory research.

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Section: Discussionmentioning

confidence: 99%

Selection of suitable reference genes for gene expression studies in HMC3 cell line by quantitative real-time RT-PCR

Fazzina,

Bergonzoni,

Massenzio

et al. 2024

Sci Rep

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“…In addition, the TREM2 gene may be a source of epigenetic regulators aimed at self-regulation or modulation of other genes' expression [66][67][68][69][70][71][72]. Recently, circRNAs have emerged as interesting molecules that deserve to be investigated as epigenetic regulators [73].…”

Section: Discussionmentioning

confidence: 99%

TREM2 Expression and Amyloid-Beta Phagocytosis in Alzheimer’s Disease

Rosa

Agostini

Piancone

et al. 2023

IJMS

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Alzheimer’s Disease is the most common form of dementia; its key pathological findings include the deposition of extracellular-neurotoxic-plaques composed of amyloid-beta (Ab). AD-pathogenesis involves mechanisms that operate outside the brain, and new researches indicate that peripheral inflammation is an early event in the disease. Herein, we focus on a receptor known as triggering-receptor-expressed-on-myeloid-cells2 (TREM2), which promotes the optimal immune cells function required to attenuate AD-progression and is, therefore, a potential target as peripheral diagnostic and prognostic-biomarker for Alzheimer’s Disease. The objective of this exploratory study was to analyze: (1) soluble-TREM2 (sTREM2) plasma and cerebrospinal fluid concentration, (2) TREM2-mRNA, (3) the percentage of TREM2-expressing monocytes, and (4) the concentration of miR-146a-5p and miR-34a-5p suspected to influence TREM2 transcription. Experiments were performed on PBMC collected by 15AD patients and 12age-matched healthy controls that were unstimulated or treated in inflammatory (LPS) conditions and Ab42 for 24 h; Aβ42-phagocytosis was also analyzed by AMNIS FlowSight. Results although preliminary, due to limitations by the small sample-size, showed that in AD compared to HC: TREM2 expressing monocytes were reduced, plasma sTREM2 concentration and TREM2-mRNA were significantly upregulated and Ab42-phagocytosis was diminished (for all p < 0.05). miR-34a-5p expression was reduced (p = 0.02) as well in PBMC of AD, and miR-146 was only observed in AD cells (p = 0.0001).

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“…circ-Epc1 may regulate TREM2 by sponging miR-770-3p. [ 212 ] Urdánoz-Casado et al, 2022 circTREM2_1 Not known Homo Sapiens and HMC3 cells AD circTREM2_1 expression level negatively correlated with Aβ deposits in the entorhinal cortex of AD patients [ 213 ] Li et al, 2022 circ_0004381 miR-647/PSEN1 axis Mus musculus AD model mice Knockdown of circ_0004381 promoted microglial M2-type polarization and inhibited the production of inflammatory factors by microglia. circ_0004381 regulated presenilin-1 (PSEN1) expression by absorbing miR-647 [ 214 ] Akhter et al, 2018 ciRS-7 (CDR 1as) CDR1as /miR-7/UBE2A axis Homo Sapiens AD patients CDR1as can lead to a decrease in miR-7 expression, which upregulates the activity of UBE2A [ 215 ] Xu et al, 2022 circ_0005835 circ_0005835/ miR-576-3p Homo Sapiens, SH-SY5Y and BV2 cells AD, Aβ-treated in both SH-SY5Y and BV2 cells Knockdown of circ_0005835 could downregulate neuroinflammation through sponging miR-576-3p in BV2 cells [ 216 ] Li et al, 2022 circ-AXL Circ-AXL /miR-328 /BACE1 axis SK-N-SH and SK-SY5Y cell lines AD models Circ-AXL overexpression increased apoptosis rate and declined neurite outgrowth, as well as elevated inflammatory cytokines.…”

Section: Non-coding Rna and Microglia Activation And Neuroinflammationmentioning

confidence: 99%

“…Intriguingly, the expression levels of circTREM2_1, but not TREM2 mRNA, demonstrated a negative correlation with the accumulation of Aβ deposits in the entorhinal cortex of AD patients. 213 …”

Section: Non-coding Rna and Microglia Activation And Neuroinflammationmentioning

confidence: 99%

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

He,

Li,

Yang

et al. 2023

JIR

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by complex pathophysiological features. Amyloid plaques resulting from extracellular amyloid deposition and neurofibrillary tangles formed by intracellular hyperphosphorylated tau accumulation serve as primary neuropathological criteria for AD diagnosis. The activation of microglia has been closely associated with these pathological manifestations. Non-coding RNA (ncRNA), a versatile molecule involved in various cellular functions such as genetic information storage and transport, as well as catalysis of biochemical reactions, plays a crucial role in microglial activation. This review aims to investigate the regulatory role of ncRNAs in protein expression by directly targeting genes, proteins, and interactions. Furthermore, it explores the ability of ncRNAs to modulate inflammatory pathways, influence the expression of inflammatory factors, and regulate microglia activation, all of which contribute to neuroinflammation and AD. However, there are still significant controversies surrounding microglial activation and polarization. The categorization into M1 and M2 phenotypes may oversimplify the intricate and multifaceted regulatory processes in microglial response to neuroinflammation. Limited research has been conducted on the role of ncRNAs in regulating microglial activation and inducing distinct polarization states in the context of neuroinflammation. Moreover, the regulatory mechanisms through which ncRNAs govern microglial function continue to be refined. The current understanding of ncRNA regulatory pathways involved in microglial activation remains incomplete and may be influenced by spatial, temporal, and tissue-specific factors. Therefore, further in-depth investigations are warranted. In conclusion, there are ongoing debates and uncertainties regarding the activation and polarization of microglial cells, particularly concerning the categorization into M1 and M2 phenotypes. The study of ncRNA regulation in microglial activation and polarization, as well as its mechanisms, is still in its early stages and requires further investigation. However, this review offers new insights and opportunities for therapeutic approaches in AD. The development of ncRNA-based drugs may hold promise as a new direction in AD treatment.

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Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Cited by 7 publications

References 82 publications

Selection of suitable reference genes for gene expression studies in HMC3 cell line by quantitative real-time RT-PCR

Selection of suitable reference genes for gene expression studies in HMC3 cell line by quantitative real-time RT-PCR

TREM2 Expression and Amyloid-Beta Phagocytosis in Alzheimer’s Disease

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

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