title: A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation.
abstract: Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer 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 betaA4 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.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, University of Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Angulo
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Carmen
authors.initials: C
authors.lastname: Lluis
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D014178:Translocation, Genetic; D014404:Tubulin / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D014404:Tubulin; D014970:Xanthines; D016875:tau Proteins; C047235:N-(1-methyl-2-phenylethyl)adenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one