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Published Erratum
. 2016 Aug;21(8):1153-4.
doi: 10.1038/mp.2015.215. Epub 2016 Jan 19.

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

B Readhead, J-V Haure-Mirande, B Zhang, V Haroutunian, S Gandy, E E Schadt, J T Dudley, M E Ehrlich
Published Erratum

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

B Readhead et al. Mol Psychiatry. 2016 Aug.
No abstract available

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Figures

Figure 3.
Figure 3.
Multiregion transcriptome comparisons between fibrillogenic, oligomerogenic and wild-type mice implicates amyloid/Aβ processing, extracellular matrix (ECM) regulation and neurogenesis (a, b–i) Fragile X Mental Retardation 1 (FMR1) gene is differentially spliced in fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q dentate gyrus (also vs wild type), as well as multiple brain regions in LOAD and (b-ii) is a known regulator of APP, binding to mRNA in the post-synaptic neuron in an mGluR5 stimulation-dependent manner. (b-iii) DE genes in both comparisons with wild type (see Figure 2), are enriched for known protein interactors of APP. APP interactors that are DE in the fibrillogenic APPKM670/671NL/PSEN1Δexon9DG vs wild type are shown. (b-iv) Adaptor protein GRB2 is differentially spliced in fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q dentate gyrus, and interacts with APP and PSEN1, localized to the centrosomes, resulting in ERK1/2 activation, and potentiation of oligomer-induced toxicity. (c) ECM regulation was a recurring theme of the pathway analysis following differential gene and exon expression analysis. (c-i) Known ECM regulators that are differentially expressed in fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild-type mice (dentate gyrus) suggest mechanisms of perturbation and compensation. (c-ii) Gene Ontology (GO) enrichment analysis of the 354 genes that are differentially expressed in fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild-type mice (dentate gyrus) demonstrate that the trend toward ECM disruption is particularly strong in this comparison. (d) Pathway enrichment analysis of the differentially expressed genes in fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild-type mice (dentate gyrus) indicates perturbation of stem cell, neural progenitor cell and neurogenesis pathways. (d-i) SUZ12 is a key member of the polycomb repressive complex 2 (PRC2), and is differentially spliced in fibrillogenic APPKM670/671NL/PSEN1Δexon9 mice vs oligomerogenic APPE693Q dentate gyrus (and also vs wild type). (d-ii) A functional role for SUZ12 is strongly supported by enrichment analysis of ChipSeq-based transcription factor gene targets, with the 354 differentially expressed genes in fibrillogenic APPKM670/671NL/PSEN1Δexon9 vs wild-type mice (dentate gyrus). (d-iii) SUZ12 function within the PRC2 is associated with regulation of neurogenic differentiation of stem cells via histone H3K27 and H3K9 methylation. (e-i) Zinc finger gene SP1 was identified as the transcription factor most strongly enriched for DEX genes (APPKM670/671NL/PSEN1Δexon9 vs wild-type comparison). (e-ii) SP1 is a transcriptional regulator of multiple AD-associated genes, and forms a potential link between these molecular nodes and the main DEX themes we have discussed, including perturbations in neurogenesis, amyloid processing and ECM regulation.
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