title: Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models.
abstract: In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Martiskainen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Viswanathan
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Niko-Petteri
authors.initials: NP
authors.lastname: Nykänen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Mitja
authors.initials: M
authors.lastname: Kurki
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kaisa M A
authors.initials: KM
authors.lastname: Kurkinen
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.affiliation: Department of Pathology, Kuopio University Hospital, Kuopio, Finland; Institute of Clinical Medicine-Pathology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Rauramaa
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Institute of Clinical Medicine-Neurosurgery, University of Eastern Finland, Kuopio, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.affiliation: Institute of Clinical Medicine-Neurosurgery, University of Eastern Finland, Kuopio, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Huttunen
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. Electronic address: mikko.hiltunen@uef.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009454:Neurofibrils / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012306:Risk; D059467:Transcriptome / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C101410:BIN1 protein, human; C574784:FERM domain-containing protein 4A, human; C574492:MS4A6A protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Neurofibrillary pathology; Pathway analysis; Risk genes; Transcriptomics