A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and Translocation

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH‐SY5Y cell line, agonists for A1R led to a dose‐dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK‐dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.

[1]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[2]  W. Neupert,et al.  Deficiency in mRNA splicing in a cytochrome c mutant of neurospora crassa: importance of carboxy terminus for import of apocytochrome c into mitochondria. , 1987, The EMBO journal.

[3]  P. Greengard,et al.  Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Cohen,et al.  p42 map kinase phosphorylation sites in microtubule‐associated protein tau are dephosphorylated by protein phosphatase 2A1 Implications for Alzheimer's disease , 1992, FEBS letters.

[5]  G. Drewes,et al.  Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state. , 1992, The EMBO journal.

[6]  J. Ávila,et al.  Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease , 1992, FEBS letters.

[7]  S. Sahasrabudhe,et al.  The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment. , 1994, The Journal of biological chemistry.

[8]  F. Ciruela,et al.  Immunological identification of A1 adenosine receptors in brain cortex , 1995, Journal of neuroscience research.

[9]  R. Wurtman,et al.  Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G. Drewes,et al.  Structure, Microtubule Interactions, and Phosphorylation of Tau Protein a , 1996, Annals of the New York Academy of Sciences.

[11]  S. Lovestone,et al.  The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. , 1997, Neuroscience.

[12]  J. Bos,et al.  Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras , 1997, Oncogene.

[13]  R. Wurtman,et al.  Metabotropic Glutamate Receptor Subtype mGluR1α Stimulates the Secretion of the Amyloid β‐Protein Precursor Ectodomain , 1997 .

[14]  J. Growdon,et al.  Metabotropic glutamate receptor subtype mGluR1alpha stimulates the secretion of the amyloid beta-protein precursor ectodomain. , 1997, Journal of neurochemistry.

[15]  S. Gauthier,et al.  Alzheimer's disease: current knowledge, management and research. , 1997, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[16]  Veeranna,et al.  Mitogen-Activated Protein Kinases (Erk1,2) Phosphorylate Lys-Ser-Pro (KSP) Repeats in Neurofilament Proteins NF-H and NF-M , 1998, The Journal of Neuroscience.

[17]  D. Stephenson,et al.  Metabotropic glutamate receptor activation in vivo induces intraneuronal amyloid immunoreactivity in guinea pig hippocampus , 1998, Neurochemistry International.

[18]  Gerhard Ransmayr,et al.  Loss of human hippocampal adenosine A1 receptors in dementia: evidence for lack of specificity , 1998, Neuroscience Letters.

[19]  I. Lieberburg,et al.  Cellular mechanisms of beta-amyloid production and secretion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  N. Holbrook,et al.  Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. , 1999, Neuroreport.

[21]  B. Hyman,et al.  Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: implications for MAP kinase activation in Alzheimer disease. , 1999, Journal of neuropathology and experimental neurology.

[22]  J. Morrison,et al.  Neurodegenerative and age-related changes in structure and function of cerebral cortex , 1999 .

[23]  H. Braak,et al.  Temporal Sequence of Alzheimer’s Disease-Related Pathology , 1999 .

[24]  B. Strooper,et al.  Proteolytic processing and cell biological functions of the amyloid precursor protein. , 2000, Journal of cell science.

[25]  B. Wolf,et al.  Protein kinase C regulation of intracellular and cell surface amyloid precursor protein (APP) cleavage in CHO695 cells. , 2000, Biochemistry.

[26]  F. Ciruela,et al.  The Heat Shock Cognate Protein hsc73 Assembles with A1 Adenosine Receptors To Form Functional Modules in the Cell Membrane , 2000, Molecular and Cellular Biology.

[27]  G. Drewes,et al.  Microtubule‐Affinity Regulating Kinase (MARK) Is Tightly Associated with Neurofibrillary Tangles in Alzheimer Brain: A Fluorescence Resonance Energy Transfer Study , 2000, Journal of Neuropathology and Experimental Neurology.

[28]  E I Canela,et al.  Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  G. Johnson,et al.  Modulation of tau phosphorylation and intracellular localization by cellular stress. , 2000, The Biochemical journal.

[30]  Patrick R. Hof,et al.  Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 1 These authors contributed equally to this work. , 2000, Brain Research Reviews.

[31]  George Perry,et al.  Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle‐Related Events in Alzheimer Disease , 2000 .

[32]  B. Fredholm,et al.  Human adenosine A(1), A(2A), A(2B), and A(3) receptors expressed in Chinese hamster ovary cells all mediate the phosphorylation of extracellular-regulated kinase 1/2. , 2000, Molecular pharmacology.

[33]  Mauro Papotti,et al.  Immunohistochemical localization of adenosine A1 receptors in human brain regions , 2001, Neuroscience Letters.

[34]  T. Dunwiddie,et al.  The Role and Regulation of Adenosine in the Central Nervous System , 2022 .

[35]  Lars Bertram,et al.  New Frontiers in Alzheimer's Disease Genetics , 2001, Neuron.

[36]  I. Ferrer,et al.  Phosphorylated Map Kinase (ERK1, ERK2) Expression is Associated with Early Tau Deposition in Neurones and Glial Cells, but not with Increased Nuclear DNA Vulnerability and Cell Death, in Alzheimer Disease, Pick's Disease, Progressive Supranuclear Palsy and Corticobasal Degeneration , 2001, Brain pathology.

[37]  H. Shibasaki,et al.  α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity* , 2001, The Journal of Biological Chemistry.

[38]  Xiongwei Zhu,et al.  Activation and redistribution of c‐Jun N‐terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease , 2001, Journal of neurochemistry.

[39]  I. Ferrer,et al.  Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies , 2001, Journal of Neural Transmission.

[40]  H Shibasaki,et al.  alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. , 2001, The Journal of biological chemistry.

[41]  C. Haass,et al.  The cell biology of Alzheimer's disease: uncovering the secrets of secretases , 2001, Current Opinion in Neurobiology.

[42]  K. Fuxe,et al.  Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: Implications for striatal neuronal function , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Simon Lovestone,et al.  Alzheimer's disease – do tauists and baptists finally shake hands? , 2002, Trends in Neurosciences.

[44]  M. Freissmuth,et al.  Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. , 2002, Cellular signalling.

[45]  M. Barrachina,et al.  MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. , 2002, Brain research.

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

[47]  B. Winblad,et al.  Loss of stimulatory effect of guanosine triphosphate on [35S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield , 2002, Journal of neuroscience research.

[48]  A. Granholm,et al.  Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh , 2002, Trends in Neurosciences.

[49]  M. Barrachina,et al.  MPP+ increases α-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells , 2002, Brain Research.