scholarly journals A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease

2017 ◽  
Author(s):  
Kuan-lin Huang ◽  
Edoardo Marcora ◽  
Anna A Pimenova ◽  
Antonio F Di Narzo ◽  
Manav Kapoor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Age At Onset ◽  
Myeloid Cell ◽  
Cell Types ◽  
A Genome ◽  
Monocytes And Macrophages ◽  
And Function

AbstractA genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

scholarly journals Promoter methylation and gene expression of Pin1 is associated to the risk of Alzheimer's disease in Southern Chinese

2020 ◽  
Author(s):  
Suk Ling Ma ◽  
Nelson Leung Sang Tang ◽  
Linda Chiu Wa Lam
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Protective Factor ◽  
Age At Onset ◽  
Melting Curve ◽  
Melting Curve Analysis ◽  
Southern Chinese ◽  
Normal Controls

Background: Pin1 is a propyl cis-trans isomerase and it has been associated with age-at-onset of Alzheimer's disease (AD) and other pathological characteristic of AD. DNA methylation is one of the gene regulation and it might affect the gene expression. Objectives: This study was aimed to examine the correlation between DNA methylation and gene expression of Pin1 and its effect on the risk of AD in a Chinese population. Methods: 80 AD patients and 180 normal controls were recruited in this study and their cognitive function were assessed. Pin1 gene expression and methylation were quantified by real-time RT-PCR and Melting Curve Analysis-Methylation assay (MCA-Meth) respectively. Results: Our finding revealed a positive correlation between methylation and gene expression of Pin1 (p=0.001) and increased Pin1 methylation was predisposed to the risk of AD (p<0.001). CG genotype of Pin1 SNP rs2287839 was associated with higher gene expression of Pin1 (p=0.036) and the effect was only prominent in normal controls as AD patients were already methylated at Pin1 promoter. Furthermore, methylation of Pin1 was associated with better performance in cognition (p=0.018). Conclusions: Our result further supported the involvement of Pin1 in AD and the increased level of Pin1 might be a protective factor for AD.

scholarly journals The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

2019 ◽  
Vol 11 (505) ◽  
pp. eaau2291 ◽  
Author(s):  
Yuetiva Deming ◽  
Fabia Filipello ◽  
Francesca Cignarella ◽  
Claudia Cantoni ◽  
Simon Hsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Critical Role ◽  
Age At Onset ◽  
Mechanistic Explanation ◽  
Genetic Modifiers ◽  
A Genome

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

scholarly journals Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

2019 ◽  
Vol 8 (5) ◽  
pp. 651 ◽  
Author(s):  
Karan Govindpani ◽  
Laura G McNamara ◽  
Nicholas R Smith ◽  
Chitra Vinnakota ◽  
Henry J Waldvogel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Apoe Genotype ◽  
Cell Types ◽  
Pathological Process ◽  
Vascular Pathology ◽  
Amyloid Toxicity

Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

scholarly journals TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variantTrem2R47Hon murine myeloid cell function

2018 ◽  
Vol 293 (32) ◽  
pp. 12620-12633 ◽  
Author(s):  
Qingwen Cheng ◽  
Jean Danao ◽  
Santosh Talreja ◽  
Paul Wen ◽  
Jun Yin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Myeloid Cell ◽  
Pleiotropic Effects

scholarly journals Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Diego Marques-Coelho ◽  
◽  
Lukas da Cruz Carvalho Iohan ◽  
Ana Raquel Melo de Farias ◽  
Amandine Flaig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Expression ◽  
Cell Types ◽  
Brain Regions ◽  
Adult Brain ◽  
Gene Transcript ◽  
Comprehensive Overview ◽  
Gene Expression Alterations

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.

scholarly journals Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

2018 ◽  
Author(s):  
Neha S. Raghavan ◽  
Adam M. Brickman ◽  
Howard Andrews ◽  
Jennifer J. Manly ◽  
Nicole Schupf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Age At Onset ◽  
Genomic Medicine ◽  
Loss Of Function ◽  
Whole Exome ◽  
A Genome

AbstractObjectiveThe genetic bases of Alzheimer’s disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer’s disease using whole exome sequencing in 20,197 individuals.MethodsWe used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer’s Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.ResultsWe identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (p = 2.17 × 10-8; OR 36.2 [95%CI 5.8 – 1493.0]). Age-at-onset was seven years earlier for patients with SORL1 qualifying variant compared with non-carriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP, WDR76 and GRN, were among candidates for follow-up studies.InterpretationThis study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer’s disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer’s disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer’s disease in a large whole-exome study of unrelated cases and controls.

scholarly journals Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 798 ◽  
Author(s):  
Chew ◽  
Petretto
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcriptional Profiling ◽  
Cell Types ◽  
Transcriptional Networks ◽  
Network Analyses ◽  
The Central Nervous System ◽  
Mapping Gene ◽  
Transcriptomic Studies

Microglia, the main immune cells of the central nervous system, are increasingly implicated in Alzheimer’s disease (AD). Manifold transcriptomic studies in the brain have not only highlighted microglia’s role in AD pathogenesis, but also mapped crucial pathological processes and identified new therapeutic targets. An important component of many of these transcriptomic studies is the investigation of gene expression networks in AD brain, which has provided important new insights into how coordinated gene regulatory programs in microglia (and other cell types) underlie AD pathogenesis. Given the rapid technological advancements in transcriptional profiling, spanning from microarrays to single-cell RNA sequencing (scRNA-seq), tools used for mapping gene expression networks have evolved to keep pace with the unique features of each transcriptomic platform. In this article, we review the trajectory of transcriptomic network analyses in AD from brain to microglia, highlighting the corresponding methodological developments. Lastly, we discuss examples of how transcriptional network analysis provides new insights into AD mechanisms and pathogenesis.

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