TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer’s Disease and Schizophrenia

TREM2 and TYROBP are causal genes for Nasu–Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer’s disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. Methods: We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. Results: No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P < 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. Conclusion: TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.

[1]  H. Al-Hakeim,et al.  IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. , 2015, Journal of affective disorders.

[2]  Shin-ya Watanabe,et al.  Biological tests for major depressive disorder that involve leukocyte gene expression assays. , 2015, Journal of psychiatric research.

[3]  R. Yolken,et al.  Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation , 2015, PloS one.

[4]  M. Xie,et al.  TREM2 regulates microglial cell activation in response to demyelination in vivo , 2015, Acta Neuropathologica.

[5]  L. Lue,et al.  TREM2 Protein Expression Changes Correlate with Alzheimer's Disease Neurodegenerative Pathologies in Post‐Mortem Temporal Cortices , 2014, Brain pathology.

[6]  S. Hickman,et al.  TREM2 and the neuroimmunology of Alzheimer's disease. , 2014, Biochemical pharmacology.

[7]  A. Pestronk,et al.  TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. , 2014, JAMA neurology.

[8]  L. Tan,et al.  Increased expression of TREM2 in peripheral blood of Alzheimer's disease patients. , 2013, Journal of Alzheimer's disease : JAD.

[9]  Jason J. Corneveaux,et al.  Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease , 2013, Neurobiology of Aging.

[10]  R. Petersen,et al.  neurodegeneration : evidence for association of the p . R 47 H variant with frontotemporal dementia and Parkinson ¿ s disease Permalink , 2013 .

[11]  M. Jurkowska,et al.  Structure, expression pattern and biological activity of molecular complex TREM-2/DAP12. , 2013, Human immunology.

[12]  T. Sakurai,et al.  Roles of glial cells in schizophrenia: Possible targets for therapeutic approaches , 2013, Neurobiology of Disease.

[13]  Takahiro A. Kato,et al.  Neuroinflammation in schizophrenia especially focused on the role of microglia , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  F. Dickerson,et al.  C-reactive protein is elevated in schizophrenia , 2013, Schizophrenia Research.

[15]  A. Singleton,et al.  TREM2 variants in Alzheimer's disease. , 2013, The New England journal of medicine.

[16]  Joanna Masel,et al.  Genetic drift , 2011, Current Biology.

[17]  N. Uranova,et al.  Ultrastructural Alterations of Myelinated Fibers and Oligodendrocytes in the Prefrontal Cortex in Schizophrenia: A Postmortem Morphometric Study , 2011, Schizophrenia research and treatment.

[18]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[19]  Rudi A. Dierckx,et al.  Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study , 2009, Journal of Nuclear Medicine.

[20]  I. Bechmann,et al.  TREM2 is upregulated in amyloid plaque‐associated microglia in aged APP23 transgenic mice , 2008, Glia.

[21]  E. Chouery,et al.  Mutations in TREM2 lead to pure early‐onset dementia without bone cysts , 2008, Human mutation.

[22]  W. Ollier,et al.  Successful downstream application of the Paxgene Blood RNA system from small blood samples in paediatric patients for quantitative PCR analysis , 2007, BMC Immunology.

[23]  H. Neumann,et al.  Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis , 2007, Journal of Neuroimmunology.

[24]  L. Peltonen,et al.  Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS , 2005, Neurobiology of Disease.

[25]  H. Neumann,et al.  Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2 , 2005, The Journal of experimental medicine.

[26]  K. Tan-Takeuchi,et al.  Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. , 2003, The Journal of clinical investigation.

[27]  M. Colonna.  DAP12 signaling: from immune cells to bone modeling and brain myelination. , 2003, The Journal of clinical investigation.

[28]  L. Peltonen,et al.  Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. , 2002, American journal of human genetics.

[29]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[30]  L. Lanier,et al.  Cloning and characterization of a novel mouse myeloid DAP12‐associated receptor family , 2001, European journal of immunology.

[31]  Jun Wu,et al.  Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells , 1998, Nature.

[32]  J. Morris.  The Clinical Dementia Rating (CDR) , 1993, Neurology.

[33]  S. Folstein,et al.  “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician , 1975 .

[34]  I. Kanazawa,et al.  Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. , 2014, Journal of Alzheimer's disease : JAD.

[35]  H. Hakola.  Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. , 1972, Acta psychiatrica Scandinavica. Supplementum.

[36]  Hakola Hp.  Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. , 1972 .