Altered distribution of mGlu2 receptors in β-amyloid-affected brain regions of Alzheimer cases and aged PS2APP mice

• Published in: Brain research Vol. 1363; pp. 180 - 190
• Main Authors: Richards, Grayson, Messer, Jürg, Faull, Richard L.M, Stadler, Heinz, Wichmann, Jürgen, Huguenin, Philipp, Bohrmann, Bernd, Mutel, Vincent
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 06.12.2010; Elsevier
• Subjects: Adult and adolescent clinical studies; Aged; Aged, 80 and over; Aging; Aging - metabolism; Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Amyloidosis; Animals; Biological and medical sciences; Bridged Bicyclo Compounds - metabolism; Bridged Bicyclo Compounds - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Excitatory Amino Acid Agonists - metabolism; Excitatory Amino Acid Agonists - pharmacology; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Humans; In vitro binding; Iodine Radioisotopes; LY354740; Male; Medical sciences; Metabotropic glutamate receptor; mGlu2; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Neurology; Organic mental disorders. Neuropsychology; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Perforant path; Presenilin-2 - genetics; Presenilin-2 - metabolism; PS2APP double transgenic mouse; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Quantitative receptor radioautography; Radioligand Assay; Rats; Rats, Inbred F344; Receptor agonist; Receptors, Metabotropic Glutamate - metabolism; Tritium; LY354740; secondary visual cortex, lateral area; Receptor agonist; DG; M1; M2; entorhinal cortex; SIDZ; PS2APP double transgenic mouse; primary somatosensory cortex, barrel field; CA1; S; primary somatosensory cortex; CA3; primary somatosensory cortex, dysgranular region; SI; Aging; lacunosum moleculare; AID; Alzheimer's disease; EC; molecular layer dentate gyrus; Metabotropic glutamate receptor; primary motor cortex; Quantitative receptor radioautography; Perforant path; cornu ammonis region 3; agranular insular cortex, ventral part; caudate putamen; In vitro binding; agranular insular cortex, dorsal part; CPu; subiculum; Mol; substantia innominata; presubiculum; AIV; mGlu2; PrS; V2L; dentate gyrus; secondary motor cortex; Amyloidosis; SIBF; LMol; S1; Hippocampus; cornu ammonis region 1; Agonist; Senescence; Alzheimer disease; Central nervous system; Transgenic animal; Glutamate receptor; Enzymopathy; Encephalon; Degenerative disease; Biological receptor; Nervous system diseases; Rodentia; Metabolic diseases; In vitro; mglu2 glutamate receptor; Cerebral disorder; Vertebrata; Mammalia; Metabotropic receptor; Mouse; β Amyloid protein; Central nervous system disease; Distribution
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2010.09.072

Abstract Altered glutamatergic synaptic transmission is among the key events defining the course of Alzheimer's disease (AD). mGlu2 receptors, a subtype of group II metabotropic glutamate receptors, regulate (as autoreceptors) fast synaptic transmission in the CNS via the controlled release of the excitatory amino acid glutamate. Since their pharmacological manipulation in rodents has been reported to affect cognition, they are potential drug targets for AD therapy. We examined the fate of these receptors in cases of AD as well as in aging PS2APP mice—a proposed model of the disease. In vitro binding of [3 H]LY354740, a selective group II agonist (with selective affinity for mGlu2 receptors, under the assay conditions used) and quantitative radioautography revealed a partial, but highly significant, loss of receptors in amyloid-affected discrete brain regions of AD cases and PS2APP mice. Among the mouse brain regions affected were, above all, the subiculum but also frontolateral cortex, dentate gyrus, lacunosum moleculare and caudate putamen. In AD, significant receptor losses were registered in entorhinal cortex and lacunosum moleculare (40% and 35%, respectively). These findings have implications for the development of selective ligands for symptomatic therapy in AD and for its diagnosis.