Role of amyloid β in the induction of lipolysis and secretion of adipokines from human adipose tissue

Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana; Kluftinger, Andreas; Little, Jonathan P.

doi:10.4161/21623945.2014.985020

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…Knockout (IP6K1-/-) yeast models have shown decreased mitochondrial respiration, yet increases in ATP, a paradox that is thought to be due to enhanced glycolysis and depletion of metabolic processes requiring ATP (39). Further, its role in lipolysis is pathologically relevant as findings from Wan et al (40) demonstrate the capacity of Ab accumulation to promote lipolysis, increasing lipid toxicity and lipid peroxidation, leading to subsequent downstream mitochondrial dysfunction (41), a phenotype common to many neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Silzer

Pathak

Phillips

2020

Preprint

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Background. Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. Methods. Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman’s rho. Fisher’s Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. Results. Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. Conclusion. With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Silzer

Pathak

Phillips

2020

Preprint

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“…The AD module associated with regulation of lipolysis in adipocytes and neuroactive ligand-receptor interaction was not preserved in both MCI and HC networks. Aβ, a key molecule in AD brain pathology, can induce lipolysis within human adipose tissue [40]. In addition, lipolysis is promoted by insulin resistance and in turn lipolysis generates ceramides further impairing insulin signaling, which is becoming increasingly more important in AD [41].…”

Section: Discussionmentioning

confidence: 99%

Genetic networks in Parkinson’s and Alzheimer’s disease

Kelly

Moyeed

Carroll

et al. 2020

Aging

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Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative diseases and there is increasing evidence that they share common physiological and pathological links. Here we have conducted the largest network analysis of PD and AD based on their gene expressions in blood to date. We identified modules that were not preserved between disease and healthy control (HC) networks, and important hub genes and transcription factors (TFs) in these modules. We highlighted that the PD module not preserved in HCs was associated with insulin resistance, and HDAC6 was identified as a hub gene in this module which may have the role of influencing tau phosphorylation and autophagic flux in neurodegenerative disease. The AD module associated with regulation of lipolysis in adipocytes and neuroactive ligand-receptor interaction was not preserved in healthy and mild cognitive impairment networks and the key hubs TRPC5 and BRAP identified as potential targets for therapeutic treatments of AD. Our study demonstrated that PD and AD share common disrupted genetics and identified novel pathways, hub genes and TFs that may be new areas for mechanistic study and important targets in both diseases.

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“…Knockout (IP6K1-/-) yeast models have shown decreased mitochondrial respiration, yet increases in ATP, a paradox that is thought to be due to enhanced glycolysis and depletion of metabolic processes requiring ATP (31). Further, its role in lipolysis is pathologically relevant as findings from Wan et al (32) demonstrate the capacity of Ab accumulation to promote lipolysis, increasing lipid toxicity and lipid peroxidation, leading to subsequent downstream mitochondrial dysfunction (33), a phenotype common to many neurodegenerative diseases.…”

Section: Nuclear Genes Are Associated With P9 Methylationmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Silzer

Pathak

Phillips

2020

Preprint

View full text Add to dashboard Cite

Background Methylation of mitochondrial tRNAs (mt-tRNA) at the 9 th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. Results Here we show variable methylation at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Expression of 5300 genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. The top 100 transcripts were found to be enriched for mitochondrial-related toxicity. Overrepresentation testing using the top 1000 transcripts revealed enrichment for a number of molecular processes and terms including some which were mitochondrial-related. Conclusion With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

show abstract

Role of amyloid β in the induction of lipolysis and secretion of adipokines from human adipose tissue

Cited by 12 publications

References 37 publications

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Genetic networks in Parkinson’s and Alzheimer’s disease

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

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