scholarly journals Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

2021 ◽  
Author(s):  
Karissa Barthelson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Production ◽  
Risk Allele ◽  
Disease Risk ◽  
Late Onset ◽  
Cellular Activity ◽  
Highly Active ◽  
The One ◽  
Common Molecular Basis

SummaryEnergy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains. Here, we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer’s disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain’s energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models ofAPOEalleles and found the same effect for the late onset Alzheimer’s disease risk allele ɛ4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer’s disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.

scholarly journals Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism

2021 ◽  
Author(s):  
Karissa Barthelson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Production ◽  
Risk Allele ◽  
Disease Risk ◽  
Late Onset ◽  
Cellular Activity ◽  
Highly Active ◽  
The One ◽  
Common Molecular Basis

Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains, Here we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer's disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain's energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimer's disease risk allele ε4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of zebrafish and of knock-in, single EOfAD mutation models for understanding the causes of this disease.

scholarly journals MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOE ɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium

2015 ◽  
Vol 49 (2) ◽  
pp. 343-352 ◽  
Author(s):  
Pau Pastor ◽  
Fermín Moreno ◽  
Jordi Clarimón ◽  
Agustín Ruiz ◽  
Onofre Combarros ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset

scholarly journals An APOE -independent cis -eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk

2018 ◽  
Vol 66 ◽  
pp. 178.e1-178.e8 ◽  
Author(s):  
Shuquan Rao ◽  
Mahdi Ghani ◽  
Zhiyun Guo ◽  
Yuetiva Deming ◽  
Kesheng Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset

scholarly journals SRSF1 and PTBP1 Aretrans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer’s Disease Risk

2019 ◽  
Vol 39 (18) ◽  
Author(s):  
Petra van Bergeijk ◽  
Uthpala Seneviratne ◽  
Estel Aparicio-Prat ◽  
Robert Stanton ◽  
Samuel A. Hasson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset ◽  
Splice Junction ◽  
Full Length ◽  
Receptor Expression ◽  
Genetic Associations ◽  
Rna Sequences ◽  
Exon 2

ABSTRACTA single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer’s disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3′ end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33’s regulation of microglial signaling underpinning the AD genetic associations.

scholarly journals Late Onset Alzheimer’s Disease Risk Variants in Cognitive Decline: The PATH Through Life Study

2017 ◽  
Vol 57 (2) ◽  
pp. 423-436 ◽  
Author(s):  
Shea J. Andrews ◽  
Debjani Das ◽  
Kaarin J. Anstey ◽  
Simon Easteal
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Disease Risk ◽  
Late Onset ◽  
Life Study ◽  
Risk Variants

Association of tripartite motif family-like 2 (TRIML2) polymorphisms with late-onset Alzheimer’s disease risk in a Korean population

2016 ◽  
Vol 630 ◽  
pp. 127-131 ◽  
Author(s):  
Won Sub Kang ◽  
Jin Kyung Park ◽  
Young Jong Kim ◽  
Ah Rang Cho ◽  
Hae Jeong Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset ◽  
Korean Population ◽  
Tripartite Motif

scholarly journals The Alzheimer’s disease risk factor APOE4 drives pro-inflammation in human astrocytes via HDAC-dependent repression of TAGLN3

2021 ◽  
Author(s):  
Laurie Arnaud ◽  
Philippe Benech ◽  
Louise Greetham ◽  
Delphine Stephan ◽  
Angélique Jimenez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Transcriptional Repression ◽  
Inflammatory Responses ◽  
Disease Risk ◽  
Late Onset ◽  
Patient Specific ◽  
Potential Biomarker ◽  
Induced Pluripotent

ABSTRACTThe Apolipoprotein E4 (APOE4) is the major allelic risk factor for late-onset Alzheimer’s disease (AD). APOE4 associates with a pro-inflammatory phenotype increasingly considered as critical in AD initiation and progression. Yet, the mechanisms driving an APOE4-dependent neuroinflammation remain unelucidated. Leveraging patient specific human induced Pluripotent Stem Cells (iPSCs) we demonstrate inflammatory chronicity and hyperactivated responses upon cytokines in human APOE4 astrocytes via a novel mechanism. We uncovered that APOE4 represses Transgelin 3 (TAGLN3), a new interacting partner of IκBα, thus increasing the NF-kB activity. The transcriptional repression of TAGLN3 was shown to result from an APOE4-dependent histone deacetylase (HDAC) activity. The functional relevance of TAGLN3 was demonstrated by the attenuation of APOE4-driven neuroinflammation after TAGLN3 supplementation. Importantly, TAGLN3 downregulation was confirmed in the brain of AD patients. Our findings highlight the APOE4-TAGLN3 axis as a new pathogenic pathway that paves the way for the development of therapeutics to prevent maladaptive inflammatory responses in APOE4 carriers, while placing TAGLN3 downregulation as a potential biomarker of AD.GRAPHICAL ABSTRACT

scholarly journals FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer's disease risk

2020 ◽  
Author(s):  
Neha Raghavan ◽  
Sanjeev Sariya ◽  
Annie Lee ◽  
Yizhe Gao ◽  
Dolly Reyes-Dumeyer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset ◽  
Major Pathway ◽  
Cerebrovascular Risk Factors ◽  
Interaction Factor ◽  
Gene Level ◽  
Cerebrovascular Risk

INTRODUCTION: Late-onset Alzheimer's disease (AD) frequently co-occurs with cerebrovascular disease. We hypothesized that interactions between genes and cerebrovascular risk factors (CVRFs) contribute to AD risk. METHODS: Participants age 65 years or older from five multi-ethnic cohorts (N=14,669) were included in genome-wide association meta-analyses for AD including an interaction factor for a CVRF score created from body mass index, hypertension, heart disease, and diabetes. Significant gene level results were substantiated using neuropathological and gene expression data. RESULTS: At the gene-level, FMNL2 interacted with the CVRF score to significantly modify AD risk (p= 7.7x10-7). A SNP within FRMD4B, rs1498837, was nominally significant (p=7.95x10-7). Increased FMNL2 expression was significantly associated with brain infarcts and AD. DISCUSSION: FMNL2 is highly expressed in the brain and has been associated with ischemic stroke and failures in endosomal trafficking, a major pathway in AD pathology. The results highlight an interaction between FMNL2 and CVRFs on AD susceptibility.

scholarly journals Genetic variability in response to Aβ deposition influences Alzheimer’s risk

2018 ◽  
Author(s):  
Dervis A. Salih ◽  
Sevinc Bayram ◽  
Manuel S. Guelfi ◽  
Regina Reynolds ◽  
Maryam Shoai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variability ◽  
Disease Risk ◽  
Late Onset ◽  
Association Studies ◽  
Amyloid Deposition ◽  
Genome Wide Association Studies ◽  
Statistical Comparison ◽  
Microglial Response

AbstractGenetic analysis of late-onset Alzheimer’s disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimer’s risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimer’s disease genome-wide association studies identifies 5 other genetic risk loci for the disease (OAS1, CXCL10, LAPTM5, ITGAM and LILRB4). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s risk.One Sentence SummaryIdentification of 5 new risk loci for Alzheimer’s by statistical comparison of mouse Aβ microglial response with gene-based SNPs from human GWAS

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