Genome-Wide Profiling of miRNA and mRNA Expression in Alzheimer’s Disease

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01199-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Joseph S. Reddy ◽

Mariet Allen ◽

Charlotte C. G. Ho ◽

Stephanie R. Oatman ◽

Özkan İş ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Transcriptome Profiling ◽

Brain Regions ◽

Common Finding ◽

Amyloid Angiopathy ◽

Genome Wide ◽

A Genome ◽

Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

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P2-146: APOE 4-STRATIFIED GENOME-WIDE ASSOCIATION STUDY OF LATE-ONSET ALZHEIMER'S DISEASE IN NORTHWESTERN EUROPEANS REVEALS NOVEL SUGGESTIVE PROTECTIVE LOCI

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.2553 ◽

2019 ◽

Vol 15 ◽

pp. P629-P631

Author(s):

Michael E. Belloy ◽

Valerio Napolioni ◽

Yann Le Guen ◽

Yongha Kim ◽

Michael D. Greicius

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Late Onset ◽

Genome Wide Association ◽

Genome Wide

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VariFunNet, an integrated multiscale modeling framework to study the effects of rare non-coding variants in genome-wide association studies: Applied to Alzheimer's disease

2017 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) ◽

10.1109/bibm.2017.8217995 ◽

2017 ◽

Cited By ~ 3

Author(s):

Qiao Liu ◽

Chen Chen ◽

Annie Gao ◽

Hang Hang Tong ◽

Lei Xie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multiscale Modeling ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Modeling Framework ◽

Genome Wide ◽

Multiscale Modeling Framework ◽

Coding Variants

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Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation

PLoS Genetics ◽

10.1371/journal.pgen.1004758 ◽

2014 ◽

Vol 10 (10) ◽

pp. e1004758 ◽

Cited By ~ 61

Author(s):

John S. K. Kauwe ◽

Matthew H. Bailey ◽

Perry G. Ridge ◽

Rachel Perry ◽

Mark E. Wadsworth ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

Csf Levels

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Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x19666210826130210 ◽

2021 ◽

Vol 19 ◽

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Maroua Jalouli ◽

Md. Ataur Rahman ◽

Philippe Jeandet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Innate Immune ◽

Misfolded Proteins ◽

Inflammatory Signaling ◽

Genome Wide Analysis ◽

Genome Wide ◽

Immunological Mechanisms ◽

The Brain

: Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can in turn induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.

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Genetic effect estimates in case-control studies when a continuous variable is omitted from the model

10.1101/756015 ◽

2019 ◽

Author(s):

Ying Sheng ◽

Chiung-Yu Huang ◽

Siarhei Lobach ◽

Lydia Zablotska ◽

Iryna Lobach ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

False Positive Rate ◽

Continuous Variable ◽

Genetic Effects ◽

Data Availability ◽

Conditional Density ◽

Link Type ◽

Genome Wide

ABSTRACTLarge-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over-estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimer’s disease.Data Availability StatementThe data that support the findings of this study are openly available in the Database of Genotypes and Phenotypes at [https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000372.v1.p1], reference number [phs000372.v1.p1] and at the Alzheimer’s Disease Neuroimaging Initiative http://adni.loni.usc.edu/.

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