Molecular systems evaluation of oligomerogenic APPE693Q and fibrillogenic APPKM670/671NL/PSEN1Δexon9 mouse models identifies shared features with human Alzheimer’s brain molecular pathology

Nov 11, 2015Molecular psychiatry

Molecular system analysis of two Alzheimer’s mouse models reveals shared features with human Alzheimer's brain changes

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Abstract

Differential gene expression analysis identified significant alterations in APP/Aβ metabolism in two distinct mouse models of Alzheimer's disease.

Two mouse models expressing different mutant AD-related proteins exhibited distinct pathophysiological features.
One model developed amyloid beta oligomers without fibrillar amyloid deposits, while the other accumulated fibrillar amyloid and plaques.
Integrative genomic analysis revealed alterations in pathways related to neurogenesis, cytoskeletal organization, and extracellular matrix regulation.
FMR1 was identified as a key negative regulator of APP translation and oligomer formation.
Transcriptomic findings displayed significant similarities with human Alzheimer's disease gene networks and dysregulated pathways.

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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.

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354

Differentially Expressed Genes in Fibrillogenic Model

Identified in the dentate gyrus vs. wild-type mice.

Differentially Expressed Genes in Oligomerogenic Model

Identified in the entorhinal cortex vs. wild-type mice.

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Molecular systems evaluation of oligomerogenic APPE693Q and fibrillogenic APPKM670/671NL/PSEN1Δexon9 mouse models identifies shared features with human Alzheimer’s brain molecular pathology

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