title: 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.
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.
authors.affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Readhead
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J-V
authors.initials: JV
authors.lastname: Haure-Mirande
authors.affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|James J. Peters VA Medical Center, New York, NY, USA.|Center for Cognitive Health and NFL Neurological Care, Department of Neurology, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gandy
authors.affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Ehrlich
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D024022:Fibrillar Collagens; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics*; D012307:Risk Factors; D059467:Transcriptome / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D024022:Fibrillar Collagens; D051860:Fragile X Messenger Ribonucleoprotein 1; D053764:Presenilin-1; C497684:Fmr1 protein, mouse