Comorbidity Analysis between Alzheimer’s Disease and Type 2 Diabetes Mellitus (T2DM) Based on Shared Pathways and the Role of T2DM Drugs

Karki, Reagon; Kodamullil, Alpha Tom; Hofmann‐Apitius, Martin

doi:10.3233/jad-170440

Cited by 55 publications

(43 citation statements)

References 62 publications

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“…This is not surprising since protein kinases in this pathway regulate many cellular activities including cellular differentiation, proliferation, apoptosis, inflammation, and innate immunity [45]. In AD, the crosstalk between insulin and MAPK signaling pathways may play a role in the disease pathogenesis [37,46]. Similar pathways crosstalk may be involved in the pathogenesis of FTD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Santiago¹,

Bottero

Potashkin

2020

IJMS

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Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Santiago¹,

Bottero

Potashkin

2020

IJMS

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“…A number of mTOR-autophagy modulators have been shown to have positive effects on cognitive decline. The mTOR inhibition triggers autophagy to decrease Ab and improve T2DM and AD memory impairment (55). LC3, which is associated with the autophagosome from its formation to its maturation into autolysosome, serves as a marker for autophagy (56).…”

Section: Discussionmentioning

confidence: 99%

Effect of the ZiBuPiYin Recipe on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats After Chronic Psychological Stress

Zhan

Zhou

et al. 2020

Front. Psychiatry

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Background: Cognitive impairment is a complication of type 2 diabetes mellitus (T2DM) that affects the central nervous system (CNS). Studies have shown that chronic psychological stress may promote the development of T2DM into diabetes-associated cognitive decline (DACD). Previously, cognitive impairment in T2DM was correlated predominantly with insulin resistance in the medial prefrontal cortex (mPFC). Aims:We examined the effect of the ZiBuPiYin recipe (ZBPYR) on Zucker diabetic fatty (ZDF) rats and explored the impact of chronic stress on altered b-amyloid (Ab) metabolism through insulin receptor substrate (IRS) 1/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway after the induction of chronic psychological stress.Main Methods: After chronic psychological stress and drug treatment, cognitive function was observed via behavioral experiments. The activation of the hypothalamus-pituitaryadrenal (HPA) axis and levels of Ab were detected by enzyme-linked immunosorbent assay, and the expression of related proteins was evaluated by Western blotting.Key Findings: ZBPYR treatment significantly decreased anxious-like behaviors and plasma corticosterone (CORT) levels, and ameliorated learning and memory impairments of ZDF rats after chronic psychological stress. ZBPYR also reduced the deposition of Ab in the mPFC, improved brain insulin resistance, and modulated the mTOR-autophagy pathway.Significance: ZBPYR may be a potential therapeutic application for the treatment of DACD induced by chronic psychological stress.

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“…The increasing evidence showed that obesity in midlife was associated with the risk of AD [5,39,40]. A wide range of studies suggest the genetic and pathological links between AD and T2D/obesity [17,40,41]. DNA methylation plays an important regulatory role in the pathogenesis of T2D, obesity and AD [11,14].…”

Section: Discussionmentioning

confidence: 99%

Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease

Liu¹,

Yu²,

Cao³

et al. 2020

Preprint

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Abstract Background: The relationship between DNA methylation, common metabolic risk and Alzheimer’s disease (AD) is not well understood.Methods: Summary statistics integrating DNA methylation quantitative trait loci (mQTLs) and several genome-wide association study data were used. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association among metabolic traits, DNA methylation and AD.Results: Our study showed that cis-mQTLs determined DNA methylation to higher total cholesterol (TC) was associated with higher AD risk (β [95% CI] =0.007 [0.002-0.013], P=0.005). The findings were robust in sensitivity analyses with different instrumental variables. We found no evidence to support causal associations of cis-mQTLs determined obesity and T2D with AD, and vice versa.Conclusion: Overall, our study showed that the cis-mQTLs determined DNA methylation to higher TC was associated with higher AD risk, whereas the relation of cis-mQTLs determined AD and metabolic dysregulation was unlikely to be causal.

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Comorbidity Analysis between Alzheimer’s Disease and Type 2 Diabetes Mellitus (T2DM) Based on Shared Pathways and the Role of T2DM Drugs

Cited by 55 publications

References 62 publications

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Effect of the ZiBuPiYin Recipe on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats After Chronic Psychological Stress

Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease

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