Genomics: New Light on Alzheimer’s Disease Research

Jung, Yeong Ju; Kim, Yoon Ha; Bhalla, Mridula; Lee, Sung Bae; Seo, Jinsoo

doi:10.3390/ijms19123771

Cited by 15 publications

(17 citation statements)

References 122 publications

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“…The genome-wide landscape of AD has been studied widely, and the gene expression patterns involved in in the process of AD have been described in detail [42,43]. However, the mechanism of functional genome alterations in AD requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model

et al. 2020

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Background: The pathological hallmarks of Alzheimer's disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility. Here, the landscape of chromatin accessibility was studied to understand the outline of the transcription and expression of AD-associated metabolism genes in an AD mouse model. Methods: The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the ADassociated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA sequencing. Gene ontology (GO) analysis was applied to elucidate biological processes and signaling pathways altered in APP/PS1 mice. Critical transcription factors were identified; alterations in chromatin accessibility were further confirmed using chromatin immunoprecipitation assays. Results: We identified 1690 increased AD-associated chromatin-accessible regions in the hippocampal tissues of APP/ PS1 mice. These regions were enriched in genes related to diverse signaling pathways, including the PI3K-Akt, Hippo, TGF-β, and Jak-Stat signaling pathways, which play essential roles in regulating cell proliferation, apoptosis, and inflammatory responses. A total of 1003 decreased chromatin-accessible regions were considered to be related with declined AD-associated biological processes including cellular response to hyperoxia and insulin stimulus, synaptic transmission, and positive regulation of autophagy. In the APP/PS1 hippocampus, 1090 genes were found to be upregulated and 1081 downregulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting upregulated mRNA levels. Several genes involved in AD development were found to have a significantly increased expression in APP/PS1 mice compared to controls, including Sele, Clec7a, Cst7, and Ccr6. The signatures of numerous transcription factors, including Olig2, NeuroD1, TCF4, and NeuroG2, were found enriched in the AD-associated accessible chromatin regions. The transcription-activating marks of H3K4me3 and H3K27ac were also found increased in the promoters of these genes. These results indicate that the mechanism for the upregulation of genes could be attributed to the enrichment of open chromatin regions with transcription factors motifs and the histone marks H3K4me3 and H3K27ac.

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Section: Discussionmentioning

confidence: 99%

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model

et al. 2020

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“…Dysregulation of lipid homeostasis and inflammation underlie the development of AD pathology [ 26 , 27 , 28 ], and type 2 diabetes increases the risk of AD [ 29 ]. However, studies on the association between ApoC3 and risk of AD are limited.…”

Section: Discussionmentioning

confidence: 99%

Urinary Apolipoprotein C3 Is a Potential Biomarker for Alzheimer’s Disease

Watanabe

Hirao

Kasuga

et al. 2020

Dement Geriatr Cogn Disord Extra

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Introduction: Biomarkers of Alzheimer’s disease (AD) that can easily be measured in routine health checkups are desirable. Urine is a source of biomarkers that can be collected easily and noninvasively. We previously reported on the comprehensive profile of the urinary proteome of AD patients and identified proteins estimated to be significantly increased or decreased in AD patients by a label-free quantification method. The present study aimed to validate urinary levels of proteins that significantly differed between AD and control samples from our proteomics study (i.e., apolipoprotein C3 [ApoC3], insulin-like growth factor-binding protein 3 [Igfbp3], and apolipoprotein D [ApoD]). Methods: Enzyme-linked immunosorbent assays (ELISAs) were performed using urine samples from the same patient and control groups analyzed in the previous proteomics study (18 AD and 18 controls, set 1) and urine samples from an independent group of AD patients and controls (13 AD, 5 mild cognitive impairment [MCI], and 32 controls) from the National Center for Geriatrics and Gerontology Biobank (set 2). Results: In set 1, the crude urinary levels of ApoD, Igfbp3, and creatinine-adjusted ApoD were significantly higher in the AD group relative to the control group (p = 0.003, p = 0.002, and p = 0.019, respectively), consistent with our previous proteomics results. In set 2, however, the crude urinary levels of Igfbp3 were significantly lower in the AD+MCI group than in the control group (p = 0.028), and the levels of ApoD and ApoC3 did not differ significantly compared to the control group. Combined analysis of all samples revealed creatinine-adjusted ApoC3 levels to be significantly higher in the AD+MCI group (p = 0.015) and the AD-only group (p = 0.011) relative to the control group. Conclusion: ApoC3 may be a potential biomarker for AD, as validated by ELISA. Further analysis of ApoC3 as a urinary biomarker for AD is warranted.

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“…The heritability for AD is between 60 and 80% ( Wingo, 2012 ). AD genetics has been reviewed elsewhere ( Reitz, 2015 ; Goldman and Van Deerlin, 2018 ; Jung et al, 2018 ). However, only 1% of all AD is autosomal dominant genes, such as presenilin 1 ( PSEN1 ), presenilin 2 ( PSEN2 ), and amyloid precursor protein ( APP ) ( Hinz and Geschwind, 2017 ).…”

Section: Genes Associated With Obesity and Neurodegenerative And Neurmentioning

confidence: 99%

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

2020

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Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin–melanocortin pathway ( LEP , LEPR , POMC , BDNF , MC4R , PCSK1 , SIM1 , BDNF , TrkB , etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity ( FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2 , among others) and with neurodegenerative or neurodevelopmental diseases ( APOE, CD38, SIRT1, TNF α, PAI-1, TREM2, SYT4, FMR1, TET3 , among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene–environment would lead to a better understanding of the etiology of these diseases.

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Genomics: New Light on Alzheimer’s Disease Research

Cited by 15 publications

References 122 publications

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model

Urinary Apolipoprotein C3 Is a Potential Biomarker for Alzheimer’s Disease

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

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