publication . Article . 2016

Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer’s disease

Laura Caberlotto; Luca Marchetti; Mario Lauria; Marco Scotti; Silvia Parolo;
Open Access English
  • Published: 02 Sep 2016 Journal: Scientific Reports (issn: 2045-2322, Copyright policy)
  • Publisher: Nature Publishing Group
Abstract
Among the genetic factors known to increase the risk of late onset Alzheimer’s diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer’s disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in ...
Subjects
free text keywords: Alzheimer disease, APOE4, computational biology, Article, Multidisciplinary, Biomarker (medicine), Genetics, Oxidative stress, medicine.disease_cause, medicine, PSEN1, Systems biology, Allele, Biology, Alzheimer's disease, medicine.disease, Notch signaling pathway, Disease
Funded by
NIH| Alzheimers Disease Neuroimaging Initiative
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01AG024904-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| National Brain and Tissue Resource for Parkinson's Disease and Related Disorders
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5U24NS072026-03
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
,
NIH| Plasma AB as a Surrogate Genetic Marker for LOAD
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01AG018023-10
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| ALZHEIMERS DISEASE PATIENT REGISTRY
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2U01AG006786-04
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| Gene discovery in PSP by transcriptome, neuropathology and sequence analysis
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3R01NS080820-02S1
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Communities
EuroMarine
European Marine Science
37 references, page 1 of 3

Corey-Bloom J. MD PhD & David R. B. Clinical Adult Neurology, 3rd Edtion. (Demos Medical Publishing, 2008).

Corder E. H.et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).8346443 [OpenAIRE] [PubMed]

Strittmatter W. J.et al.Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981 (1993).8446617 [OpenAIRE] [PubMed]

Grehan S., Tse E. & Taylor J. M. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J. Neurosci. 21, 812–822 (2001).11157067 [OpenAIRE] [PubMed]

Pitas R. E., Boyles J. K., Lee S. H., Hui D. & Weisgraber K. H. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J. Biol. Chem. 262, 14352–14360 (1987).3115992 [PubMed]

Castellano J. M.et al.Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).

Koistinaho M.et al.Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med. 10, 719–726 (2004).15195085 [OpenAIRE] [PubMed]

Webster J. A.et al.Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet.84, 445–458 (2009).19361613 [OpenAIRE] [PubMed]

Davis S. & Meltzer P. S. GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 23, 1846–1847 (2007).17496320 [PubMed]

Smyth G. K.Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).16646809 [PubMed]

Simpson J. E.et al.Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol. Aging 32, 1795–1807 (2011).21705112 [PubMed]

Lauria M., Moyseos P. & Priami C. SCUDO: a tool for signature-based clustering of expression profiles. Nucleic Acids Res. 43, W188–W192 (2015).25958391 [OpenAIRE] [PubMed]

Lauria M.Rank-based transcriptional signatures: a novel approach to diagnostic biomarker definition and analysis. Syst. Biomed. 1, 35–46 (2013).

Komurov K., Dursun S., Erdin S. & Ram P. T. NetWalker: a contextual network analysis tool for functional genomics. BMC Genomics 13, 282 (2012).22732065 [OpenAIRE] [PubMed]

Keshava Prasad T. S.et al.Human Protein Reference Database–2009 update. Nucleic Acids Res. 37, D767–D772 (2009).18988627 [OpenAIRE] [PubMed]

37 references, page 1 of 3
Abstract
Among the genetic factors known to increase the risk of late onset Alzheimer’s diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer’s disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in ...
Subjects
free text keywords: Alzheimer disease, APOE4, computational biology, Article, Multidisciplinary, Biomarker (medicine), Genetics, Oxidative stress, medicine.disease_cause, medicine, PSEN1, Systems biology, Allele, Biology, Alzheimer's disease, medicine.disease, Notch signaling pathway, Disease
Funded by
NIH| Alzheimers Disease Neuroimaging Initiative
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01AG024904-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| National Brain and Tissue Resource for Parkinson's Disease and Related Disorders
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5U24NS072026-03
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
,
NIH| Plasma AB as a Surrogate Genetic Marker for LOAD
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01AG018023-10
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| ALZHEIMERS DISEASE PATIENT REGISTRY
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2U01AG006786-04
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| Gene discovery in PSP by transcriptome, neuropathology and sequence analysis
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3R01NS080820-02S1
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Communities
EuroMarine
European Marine Science
37 references, page 1 of 3

Corey-Bloom J. MD PhD & David R. B. Clinical Adult Neurology, 3rd Edtion. (Demos Medical Publishing, 2008).

Corder E. H.et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).8346443 [OpenAIRE] [PubMed]

Strittmatter W. J.et al.Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981 (1993).8446617 [OpenAIRE] [PubMed]

Grehan S., Tse E. & Taylor J. M. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J. Neurosci. 21, 812–822 (2001).11157067 [OpenAIRE] [PubMed]

Pitas R. E., Boyles J. K., Lee S. H., Hui D. & Weisgraber K. H. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J. Biol. Chem. 262, 14352–14360 (1987).3115992 [PubMed]

Castellano J. M.et al.Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).

Koistinaho M.et al.Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med. 10, 719–726 (2004).15195085 [OpenAIRE] [PubMed]

Webster J. A.et al.Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet.84, 445–458 (2009).19361613 [OpenAIRE] [PubMed]

Davis S. & Meltzer P. S. GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 23, 1846–1847 (2007).17496320 [PubMed]

Smyth G. K.Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).16646809 [PubMed]

Simpson J. E.et al.Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol. Aging 32, 1795–1807 (2011).21705112 [PubMed]

Lauria M., Moyseos P. & Priami C. SCUDO: a tool for signature-based clustering of expression profiles. Nucleic Acids Res. 43, W188–W192 (2015).25958391 [OpenAIRE] [PubMed]

Lauria M.Rank-based transcriptional signatures: a novel approach to diagnostic biomarker definition and analysis. Syst. Biomed. 1, 35–46 (2013).

Komurov K., Dursun S., Erdin S. & Ram P. T. NetWalker: a contextual network analysis tool for functional genomics. BMC Genomics 13, 282 (2012).22732065 [OpenAIRE] [PubMed]

Keshava Prasad T. S.et al.Human Protein Reference Database–2009 update. Nucleic Acids Res. 37, D767–D772 (2009).18988627 [OpenAIRE] [PubMed]

37 references, page 1 of 3
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