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Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, Rumbaugh M, Matsushita M, Girirajan S, Dorschner MO, Kiianitsa K, Yu CE, Brkanac Z, Garden GA, Raskind WH, Bird TD. "R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study" JAMA Neurol. 2015 Aug 1;72(8):920-7. doi: 10.1001/jamaneurol.2015.0979. Wang DB, Kinoshita Y, Kinoshita C, Uo T, Sopher BL, Cudaback E, Keene CD, Bilousova T, Gylys K, Case A, Jayadev S, Wang HG, Garden GA, Morrison RS. "Loss of endophilin-B1 exacerbates Alzheimer's disease pathology." Brain. 2015 Jul;138(Pt 7):2005-19. doi: 10.1093/brain/awv128. Epub 2015 May 16. Davis MY, Keene CD, Jayadev S, Bird T. "The co-occurrence of Alzheimer's disease and Huntington's disease: a neuropathological study of 15 elderly Huntington's disease subjects." J Huntingtons Dis. 2014;3(2):209-17. doi: 10.3233/JHD-140111. Su W, Hopkins S, Nesser NK, Sopher B, Silvestroni A, Ammanuel S, Jayadev S, Möller T, Weinstein J, Garden GA "The p53 Transcription Factor Modulates Microglia Behavior through MicroRNA-Dependent Regulation of c-Maf" J Immunol. 2014 Jan 1;192(1):358-66. doi: 10.4049/jimmunol.1301397. Jayadev S, Case A, Alajajian B, Eastman AJ, Möller T, Garden GA "Presenilin 2 influences miR146 level and activity in microglia" J Neurochem. 2013 doi: 10.1111/jnc.12400. Jayadev S, Bird TD. "Hereditary ataxias: overview." Genet Med. 2013 Sep;15(9):673-83. doi: 10.1038/gim.2013.28. Epub 2013 Mar 28. Review. Jayadev S, Nesser N, Seaburg LA, Lee R, Murphy SP, Hopkins S, Case A, Uo T, Morrison RS, Meyers S, Garden GA "The Transcription Factor p53 Influences Microglia Activation Phenotype". Glia. 2011 Oct;59(10):1402-13. Jayadev S, Nochlin D, Poorkaj P, Steinbart EJ, Mastrianni JA, Montine TJ, Ghetti B, Schellenberg GD, Bird TD, Leverenz JB. "Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype." Ann Neurol. 2011 Apr;69(4):712-20. doi: 10.1002/ana.22264. Epub 2011 Mar 17. Jayadev S, Case A, Eastman AJ, Nguyen H, Pollak J, Wiley JC, Moeller T, Morrison RS, Garden GA. "Presenilin 2 is the Predominant γ-secretase in Microglia and Modulates Cytokine Release". PLoS ONE. 2010 Dec 29;5(12):e15743. Jayadev S, Leverenz JB, Steinbart EJ, Stahl J, Klunk W, Bird TD. "Alzheimer disease phenotypes and genotypes with mutations in presenilin 2". 2010 Brain. Apr;133(Pt 4):1143-54. The Jayadev LaboratoryOur Neurogenetics laboratory studies the molecular mechanisms driving CNS and peripheral innate immune cellular phenotypes relevant to initiation or promotion of neurodegeneration. Murine CNS and systemic inflammation modelsEmploying a cell-type specific transgenic murine model expressing a familial Alzheimer Disease Presenilin 2 mutation, we study the regulation of microglial and systemic immune responses to innate immune stimulation and stroke. Microglia isolated from PSEN2 N141I mutation expressing mice have an exaggerated pro-inflammatory response, similar to those we have previously observed in PSEN2 knockout microglia, supporting a loss of function mechanism in innate immunity for PSEN2 mutations contributing to AD. Patient derived innate immune studies in ADIn parallel, our laboratory has developed methods to investigate cell-autonomous and non-cell autonomous mechanisms in vitro with human neural and glial cells. Using familial AD patient induced pluripotent stem cell lines or CRISPR/Cas9 gene edited embryonic stem cell lines we study the impact of genetic neurodegenerative disease associated microglia on inflammatory responses and neuronal health in vitro. Complementing the microglial studies we are investigating the microRNA and transcriptomic alterations in peripheral innate immune cells isolated from patients carrying a familial AD (PSEN1, PSEN2, APP) gene mutation. AD Genetic Risk in Patients and Their FamiliesDr. Jayadev is PI of the UW Alzheimer Disease Research Center's Therapeutic Pipeline Project (TPP) Genetics project, a translational study investigating the genetic contribution to Alzheimer Disease using exome and genome sequencing. The group is also studying clinical utility and patient impact of exome sequencing for subjects with early onset AD or family histories of AD. We are stratifying AD genetic risk, developing counseling methods for returning exome testing results to subjects and their families, and establishing collaborations to study functional variants in vitro. |