title: Identification of neurotoxic cytokines by profiling Alzheimer's disease tissues and neuron culture viability screening.
abstract: Alzheimer's disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Wood
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Winslow
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Proctor
authors.affiliation: James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.|C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Declan
authors.initials: D
authors.lastname: McGuone
authors.affiliation: James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.|C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mordes
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.|James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.|C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012044:Regression Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D018836:Inflammation Mediators; D015848:Interleukin-5; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A