MicroRNAs targeting Nicastrin regulate AÎ² production and are affected by target site polymorphisms

Delay, Charlotte; Dorval, Véronique; Fok, Alice; Grenier‐Boley, Benjamin; Lambert, Jean‐Charles; Hsiung, Ging-Yuek Robin; Hébert, Sébastien S.

doi:10.3389/fnmol.2014.00067

Cited by 22 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We therefore repeated the luciferase-based experiments using the full-length Nicastrin 3'UTR as before. 50 As hypothesized, miR-16 could significantly downregulate luciferase activity (Nicastrin expression) in these conditions (see Supplementary Figure S8 ).…”

Section: Resultsmentioning

confidence: 61%

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease

Parsi

Smith

Goupil

et al. 2015

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Aβ and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP) and BACE1 expression, Aβ peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a γ-secretase component involved in Aβ generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including α-Synuclein and Transferrin receptor 1. Top-ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Aβ and Tau), inflammation, and oxidative stress.

show abstract

Section: Resultsmentioning

confidence: 61%

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease

Parsi

Smith

Goupil

et al. 2015

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

show abstract

“…In our study, cells transfected with miR‐186 mimic and siRNA‐IL2 had decreased expression of IL2, JAK2, STAT3, Bax, Cleaved‐Caspase‐3, p‐STAT3, and p‐JAK2 and increased expression of Bcl‐2. MiR‐186 was previously shown to be altered in AD specimens, and miR‐186 could be an important player in AD pathology (Delay et al, ). Caspase‐3 had been significantly increased in AD (Louneva et al, ).…”

Section: Discussionmentioning

confidence: 99%

Retracted: Effect of microRNA‐186 on oxidative stress injury of neuron by targeting interleukin 2 through the janus kinase‐signal transducer and activator of transcription pathway in a rat model of Alzheimer’s disease

Wen

Wang

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Recent studies have proposed that microRNAs (miR) function as novel diagnostic and prognostic biomarkers and therapeutic targets in Alzheimer's disease (AD), a common disease among the elderly. In the current study, we aim to explore the effect of miR-186 on oxidative stress injury of neuron in rat models of AD with the involvement of the interleukin-2 (IL2) and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. AD rat models were established, and dual-luciferase reporter assay and online software were used to confirm the targeting relationship between miR-186 and IL2. Immunohistochemistry was used evaluating the positive rate of IL2. Afterward, to define the role of miR-186 in AD, miR-186, IL2, and JAK-STAT related protein (JAK2, STAT3) expressions were quantified. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide, and cell apoptosis was detected by flow cytometry. We observed downregulated miR-186 and IL2 and upregulated JAK-STAT signaling pathway related genes in AD. The overexpression of miR-186 was shown to significantly promote cell proliferation while suppressing cell apoptosis along with the expression of the IL2 and JAK-STAT signaling pathway related protein. Collectively, the key findings obtained from the current study define the potential role of miR-186 as an inhibitor of AD development by downregulation of IL2 through suppression of the JAK-STAT signaling pathway.

show abstract

“…ADAM10 is the target of miR-665 [ 11 ]. miR-24, miR-186, and miR-455 are regulators of NCT [ 12 ]. BACE1 is the target of miR-186 and miR-339 [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

Tian

Dong

et al. 2016

Nutrients

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.

show abstract

MicroRNAs targeting Nicastrin regulate AÎ² production and are affected by target site polymorphisms

Cited by 22 publications

References 25 publications

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease

Retracted: Effect of microRNA‐186 on oxidative stress injury of neuron by targeting interleukin 2 through the janus kinase‐signal transducer and activator of transcription pathway in a rat model of Alzheimer’s disease

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

Contact Info

Product

Resources

About