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Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Δexon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology.

Readhead B, Haure-Mirande JV, Zhang B, Haroutunian V, Gandy S, Schadt EE, Dudley JT, Ehrlich ME - Mol. Psychiatry (2015)

Bottom Line: We also compared these results with datasets derived from human AD brain.Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space.Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

ABSTRACT
Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APP(E693Q) inside neurons, leading to the accumulation of amyloid beta (Aβ) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APP(KM670/671NL)/PSEN1(Δexon9) in neurons and accumulates fibrillar Aβ amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aβ metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD.

No MeSH data available.


Related in: MedlinePlus

Differential gene expression and enrichment analysis summary(a) Differentially expressed genes in the entorhinal cortex of oligomerogenic APPE693Q vs Wild type mice. (b) Top differentially expressed genes in the dentate gyrus of fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild type mice. (c) Quantity of differentially expressed genes, and selected GO term enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 and oligomerogenic APPE693Q vs wild type mice. (d) Quantity of differentially expressed genes, and selected GO term and KEGG pathway enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q mice. Enrichments shown were selected for known or suspected relevance to AD pathophysiology, and bolding highlights enrichments that relate to the main biological themes also implicated by the differential exon analysis findings.(Differential expression and gene set enrichments thresholded at FDR < 0.05)
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Figure 2: Differential gene expression and enrichment analysis summary(a) Differentially expressed genes in the entorhinal cortex of oligomerogenic APPE693Q vs Wild type mice. (b) Top differentially expressed genes in the dentate gyrus of fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild type mice. (c) Quantity of differentially expressed genes, and selected GO term enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 and oligomerogenic APPE693Q vs wild type mice. (d) Quantity of differentially expressed genes, and selected GO term and KEGG pathway enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q mice. Enrichments shown were selected for known or suspected relevance to AD pathophysiology, and bolding highlights enrichments that relate to the main biological themes also implicated by the differential exon analysis findings.(Differential expression and gene set enrichments thresholded at FDR < 0.05)

Mentions: We assessed regional differential expression (DE) between oligomerogenic APPE693Q vs. wild type, APPKM670/671NL/PSEN1Δexon9 vs. wild type, and APPKM670/671NL/PSEN1Δexon9 vs. oligomerogenic APPE693Q mice. In this comparison against the wild type animals, we identified 354 DE genes (FDR < 0.05) in the DG of the fibrilllogenic APPKM670/671NL/PSEN1Δexon9 mice, and 22 DE genes (FDR < 0.05) in the EC of the oligomerogenic APPE693Q mice (Figure 2). We did not observe any DE genes in the EC of the fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice or in the DG of the oligomerogenic APPE693Q mice (See Supplementary Table 1 for full DE results). To investigate whether this difference in the amount of detected differential expression across comparisons related to differential transgene expression, we examined the expression for the human APP sequence across mouse strains. We found that in both regions and lines, there was evidence of increased expression of reads that mapped to the human APP sequence (See Figure S1), though we did not see a clear relationship between human APP expression, and the quantity of genes identified as being differentially expressed.


Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Δexon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology.

Readhead B, Haure-Mirande JV, Zhang B, Haroutunian V, Gandy S, Schadt EE, Dudley JT, Ehrlich ME - Mol. Psychiatry (2015)

Differential gene expression and enrichment analysis summary(a) Differentially expressed genes in the entorhinal cortex of oligomerogenic APPE693Q vs Wild type mice. (b) Top differentially expressed genes in the dentate gyrus of fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild type mice. (c) Quantity of differentially expressed genes, and selected GO term enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 and oligomerogenic APPE693Q vs wild type mice. (d) Quantity of differentially expressed genes, and selected GO term and KEGG pathway enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q mice. Enrichments shown were selected for known or suspected relevance to AD pathophysiology, and bolding highlights enrichments that relate to the main biological themes also implicated by the differential exon analysis findings.(Differential expression and gene set enrichments thresholded at FDR < 0.05)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4862938&req=5

Figure 2: Differential gene expression and enrichment analysis summary(a) Differentially expressed genes in the entorhinal cortex of oligomerogenic APPE693Q vs Wild type mice. (b) Top differentially expressed genes in the dentate gyrus of fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild type mice. (c) Quantity of differentially expressed genes, and selected GO term enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 and oligomerogenic APPE693Q vs wild type mice. (d) Quantity of differentially expressed genes, and selected GO term and KEGG pathway enrichments shared across regional comparisons of fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q mice. Enrichments shown were selected for known or suspected relevance to AD pathophysiology, and bolding highlights enrichments that relate to the main biological themes also implicated by the differential exon analysis findings.(Differential expression and gene set enrichments thresholded at FDR < 0.05)
Mentions: We assessed regional differential expression (DE) between oligomerogenic APPE693Q vs. wild type, APPKM670/671NL/PSEN1Δexon9 vs. wild type, and APPKM670/671NL/PSEN1Δexon9 vs. oligomerogenic APPE693Q mice. In this comparison against the wild type animals, we identified 354 DE genes (FDR < 0.05) in the DG of the fibrilllogenic APPKM670/671NL/PSEN1Δexon9 mice, and 22 DE genes (FDR < 0.05) in the EC of the oligomerogenic APPE693Q mice (Figure 2). We did not observe any DE genes in the EC of the fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice or in the DG of the oligomerogenic APPE693Q mice (See Supplementary Table 1 for full DE results). To investigate whether this difference in the amount of detected differential expression across comparisons related to differential transgene expression, we examined the expression for the human APP sequence across mouse strains. We found that in both regions and lines, there was evidence of increased expression of reads that mapped to the human APP sequence (See Figure S1), though we did not see a clear relationship between human APP expression, and the quantity of genes identified as being differentially expressed.

Bottom Line: We also compared these results with datasets derived from human AD brain.Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space.Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

ABSTRACT
Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APP(E693Q) inside neurons, leading to the accumulation of amyloid beta (Aβ) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APP(KM670/671NL)/PSEN1(Δexon9) in neurons and accumulates fibrillar Aβ amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aβ metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD.

No MeSH data available.


Related in: MedlinePlus