Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

Bae, Narkhyun; Byeon, Se Eun; Song, Jihyuk; Lee, Sang Jin; Kwon, Moosik; Mook‐Jung, Inhee; Cho, Jae Youl; Hong, Sungyoul

doi:10.1038/aps.2010.228

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…Experiments in a senescence-accelerated mouse model show that PEDF negatively regulates A β and notably reduces cognitive impairment, suggesting that PEDF might play a crucial role in the development of AD [Huang et al, 2018]. Knock-down of PIMT and treatment with AdOX significantly increase A β secretion, which serves as a negative regulator of A β peptide formation and a potential protective factor in the pathogenesis of AD [Bae et al, 2011].…”

Section: An Application To the Proteomics-radiomics Study Of Admentioning

confidence: 99%

HILAMA: High-dimensional multi-omic mediation analysis with latent confounding

Wang,

Liu,

et al. 2023

Preprint

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Motivation: The increasingly available multi-omic datasets have posed both new opportunities and challenges to the development of quantitative methods for discovering novel mechanisms in biomedical research. One natural approach to analyzing such datasets is mediation analysis originated from the causal inference literature. Mediation analysis can help unravel the mechanisms through which exposure(s) exert the effect on outcome(s). However, existing methods fail to consider the case where (1) both exposures and mediators are potentially high-dimensional and (2) it is very likely that some important confounding variables are unmeasured or latent; both issues are quite common in practice. To the best of our knowledge, however, no methods have been developed to address these challenges with statistical guarantees. Results: In this article, we propose a new method for HIgh-dimensional LAtent-confounding Mediation Analysis, abbreviated as "HILAMA", that considers both high-dimensional exposures and mediators, and more importantly, the possible existence of latent confounding variables. HILAMA achieves false discovery rate (FDR) control under finite sample size for multiple mediation effect testing. The proposed method is evaluated through extensive simulation experiments, demonstrating its improved stability in FDR control and superior power in finite sample size compared to existing competitive methods. Furthermore, our method is applied to the proteomics-radiomics data from ADNI, identifying some key proteins and brain regions relating to Alzheimer's disease. The results show that HILAMA can effectively control FDR and provide valid statistical inference for high dimensional mediation analysis with latent confounding variables. Availability: The R package HILAMA is publicly available at https://github.com/Cinbo Wang/HILAMA. Contact: cinbo_w@sjtu.edu.cn

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Section: An Application To the Proteomics-radiomics Study Of Admentioning

confidence: 99%

HILAMA: High-dimensional multi-omic mediation analysis with latent confounding

Wang,

Liu,

et al. 2023

Preprint

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“…Protein L -isoaspartyl methyltransferase (PIMT) is a ubiquitous repair enzyme that recognizes these abnormal L -isoAsp residues as its substrate and converts them back to normal aspartate residues 6 . Formation and accumulation of these isoAsp can lead to various neurodegenerative diseases and the role of PIMT associated with neurodegeneration has been reported in literature 7 – 9 .…”

Section: Introductionmentioning

confidence: 99%

Effect of gold nanoparticles on the structure and neuroprotective function of protein L-isoaspartyl methyltransferase (PIMT)

Chatterjee

Das

Ghosh

et al. 2021

Sci Rep

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Fibrillation of peptides and proteins is implicated in various neurodegenerative diseases and is a global concern. Aging leads to the formation of abnormal isoaspartate (isoAsp) residues from isomerization of normal aspartates in proteins, triggering fibril formation that leads to neurodegenerative diseases. Protein L-isoaspartyl methyltransferase (PIMT) is a repair enzyme which recognizes and converts altered isoAsp residues back to normal aspartate. Here we report the effect of gold nanoparticles (AuNPs) of different sizes on the structure and function of PIMT. Spherical AuNPs, viz. AuNS5, AuNS50 and AuNS100 (the number indicating the diameter in nm) stabilize PIMT, with AuNS100 exhibiting the best efficacy, as evident from various biophysical experiments. Isothermal titration calorimetry (ITC) revealed endothermic, but entropy driven mode of binding of PIMT with all the three AuNSs. Methyltransferase activity assay showed enhanced activity of PIMT in presence of all AuNSs, the maximum being with AuNS100. The efficacy of PIMT in presence of AuNS100 was further demonstrated by the reduction of fibrillation of Aβ42, the peptide that is implicated in Alzheimer’s disease. The enhancement of anti-fibrillation activity of PIMT with AuNS100 was confirmed from cell survival assay with PC12 derived neuronal cells against Aβ42 induced neurotoxicity.

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“…Genetic modulation of the expression or activity of α-secretases has been shown to alter the levels of cleavage products of APP processing as well as Aβ production. For instance, knockdown of ADAM10 decreases sAPPα levels in mouse primary cortical neuronal cells [6], and in HEK293 APPswe cells, L-isoaspartyl O-methyltransferase knockdown decreases ADAM10/17 expression, thereby enhancing Aβ40 levels [7]. In addition, glutamatergic neuronal activity is suppressed in ADAM17 Biology 2021, 10, 938 2 of 13 knockout mice [8].…”

Section: Introductionmentioning

confidence: 99%

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

Lee

Jeong

Park

et al. 2021

Biology

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The coenzyme Q10 analogue idebenone is an FDA-approved antioxidant that can cross the blood–brain barrier (BBB). The effects of idebenone on the pathology of Alzheimer’s disease (AD) and the underlying molecular mechanisms have not been comprehensively investigated. Here, we examined the impact of idebenone treatment on AD pathology in 5xFAD mice, a model of AD. Idebenone significantly downregulated Aβ plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the Aβ degradation enzyme NEP and α-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3βY216 levels, thereby inhibiting tau hyperphosphorylation at Thr231 and total tau levels in 5xFAD mice. Taken together, the present study indicates that idebenone modulates amyloidopathy and tauopathy in 5xFAD mice, suggesting therapeutic potential for AD.

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Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

Cited by 8 publications

References 26 publications

HILAMA: High-dimensional multi-omic mediation analysis with latent confounding

HILAMA: High-dimensional multi-omic mediation analysis with latent confounding

Effect of gold nanoparticles on the structure and neuroprotective function of protein L-isoaspartyl methyltransferase (PIMT)

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

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