Tomoregulin‐2 is found extensively in plaques in Alzheimer's disease brain

Tomoregulin (TR)2 is a transmembrane protein predominantly expressed in brain. It has a unique extracellular domain, containing epidermal growth factor‐like and follistatin‐like modules. The ectodomain is released from the cell surface, and thought to function as a neurotrophic factor and dendritogenic agent. During CNS development and in the neuronal storage disease GM2 gangliosidosis, which is characterized by ectopic dendrites, the TR2 ectodomain is present in neuronal nuclei where it may function in dendrite initiation. Data presented here demonstrate that TR2 is found extensively in Alzheimer's disease (AD) plaques. Confocal microscopy shows that TR2 is present throughout plaques. Interestingly, TR2 is absent from plaques in the presenilin‐1/amyloid precursor protein mouse model of AD. From these data, and what is known about TR2, it is hypothesized that TR2 may participate in amyloid plaque formation and contribute to the pathogenesis of AD. The human TR2 gene is located on chromosome 2q32.3, near a locus linked to Parkinson's disease. TR2 is reported to be a trophic factor for dopaminergic mesencephalic neurons.

[1]  A. Tanigami,et al.  Identification and characterization of TMEFF2, a novel survival factor for hippocampal and mesencephalic neurons. , 2000, Genomics.

[2]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[3]  P. Davies,et al.  Characterization of Pathology in Transgenic Mice Over-Expressing Human Genomic and cDNA Tau Transgenes , 2000, Neurobiology of Disease.

[4]  A. Brivanlou,et al.  Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel mechanisms. , 2003, Developmental biology.

[5]  David H. Cribbs,et al.  Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome , 2004, Neuron.

[6]  E. Mackenzie,et al.  Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription. , 2004, The Biochemical journal.

[7]  K. Flanders,et al.  Effects of transforming growth factor-beta (isoforms 1-3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures. , 1998, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  R. Mrak,et al.  Glia and their cytokines in progression of neurodegeneration , 2005, Neurobiology of Aging.

[9]  R. Tanzi,et al.  Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective , 2005, Cell.

[10]  S. Hirai,et al.  Diffuse type of senile plaques in the brains of Alzheimer-type dementia , 1988, Acta Neuropathologica.

[11]  E. Masliah,et al.  Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease , 2005, Science.

[12]  S. Hirai,et al.  A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated byβ protein immunostaining , 2004, Acta Neuropathologica.

[13]  E. Mackenzie,et al.  Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription , 2004 .

[14]  I. Kanazawa,et al.  CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC‐P/collagen type XXV , 2002, The EMBO journal.

[15]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[16]  Fran Maher,et al.  Non-Aβ Component of Alzheimer's Disease Amyloid (NAC) Revisited: NAC and α-Synuclein Are Not Associated with Aβ Amyloid , 1999 .

[17]  Brian J Cummings,et al.  Localization and Cell Association of C1q in Alzheimer's Disease Brain , 1996, Experimental Neurology.

[18]  D. Benson,et al.  Alzheimer's disease and Parkinson's disease , 1988, Neurology.

[19]  B. Liang,et al.  TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization. , 1999, Brain research. Molecular brain research.

[20]  V. Lee,et al.  Comparative epitope analysis of neuronal cytoskeletal proteins in Alzheimer's disease senile plaque neurites and neuropil threads. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[21]  N. Greig,et al.  Role of cytokines in the gene expression of amyloid beta-protein precursor: identification of a 5'-UTR-binding nuclear factor and its implications in Alzheimer's disease. , 2003, Journal of Alzheimer's disease : JAD.

[22]  L A Hansen,et al.  The importance of neuritic plaques and tangles to the development and evolution of AD , 2004, Neurology.

[23]  R. Nussbaum,et al.  Alzheimer's disease and Parkinson's disease. , 2003, The New England journal of medicine.

[24]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[25]  K. Wada,et al.  Tomoregulin ectodomain shedding by proinflammatory cytokines. , 2003, Life sciences.

[26]  H. Arai,et al.  Distribution of apolipoprotein E in senile plaques in brains with Alzheimer's disease: investigation with the confocal laser scan microscope , 1997, Brain Research.

[27]  J. Trojanowski,et al.  Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[28]  E. Tarkowski Cytokines in dementias. , 2002, Current drug targets. Inflammation and allergy.

[29]  Carol Brayne,et al.  Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease , 2005, Neuroscience Letters.

[30]  J. Jankovic,et al.  Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. , 2003, Human molecular genetics.

[31]  R. Fine,et al.  Generation of Amyloidogenic C-terminal Fragments during Rapid Axonal Transport in Vivo of -Amyloid Precursor Protein in the Optic Nerve (*) , 1995, The Journal of Biological Chemistry.

[32]  S. Carroll,et al.  Neuregulin–1 and ErbB4 Immunoreactivity Is Associated with Neuritic Plaques in Alzheimer Disease Brain and in a Transgenic Model of Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

[33]  D. Selkoe,et al.  Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons , 1995, The Journal of cell biology.

[34]  K. Flanders,et al.  Effects of Transforming Growth Factor-β (Isoforms 1–3) on Amyloid-β Deposition, Inflammation, and Cell Targeting in Organotypic Hippocampal Slice Cultures , 1998, The Journal of Neuroscience.

[35]  E. Mackenzie,et al.  Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice* , 2003, The Journal of Biological Chemistry.

[36]  E. Mackenzie,et al.  Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. , 2003, The Journal of biological chemistry.

[37]  Chenbei Chang,et al.  Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto. , 2003, Genes & development.

[38]  B. Liang,et al.  Transcriptional activation and increase in expression of Alzheimer's β-amyloid precursor protein gene is mediated by TGF-β in normal human astrocytes , 2002 .

[39]  B. Dubois,et al.  Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. , 1999, American journal of human genetics.

[40]  Tony Wyss-Coray,et al.  Transforming growth factor-β signaling pathway as a therapeutic target in neurodegeneration , 2007, Journal of Molecular Neuroscience.

[41]  Denis Vivien,et al.  Cytokines in neuroinflammation and Alzheimer's disease. , 2004, Current drug targets.

[42]  E. Masliah,et al.  Structural basis of the cognitive alterations in Alzheimer disease. , 1994 .

[43]  V. Nguyen,et al.  Immunological aspects of microglia: relevance to Alzheimer's disease , 2001, Neurochemistry International.

[44]  D. Holtzman,et al.  Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. , 2005, The Journal of clinical investigation.

[45]  B. Liang,et al.  Transcriptional activation and increase in expression of Alzheimer's beta-amyloid precursor protein gene is mediated by TGF-beta in normal human astrocytes. , 2002, Biochemical and biophysical research communications.

[46]  L. Seeberger,et al.  Significant linkage of Parkinson disease to chromosome 2q36-37. , 2003, American journal of human genetics.

[47]  D. Siegel,et al.  Ectopic dendrite initiation: CNS pathogenesis as a model of CNS development , 2002, International Journal of Developmental Neuroscience.

[48]  J. Wegiel,et al.  The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APPSW mice , 2001, Neurobiology of Aging.

[49]  K. Davis,et al.  Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. , 1998, Archives of neurology.

[50]  D. Selkoe Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[51]  M. Kasuga,et al.  A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells. , 1999, Biochemical and biophysical research communications.

[52]  C. Masters,et al.  Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. , 1999, The American journal of pathology.