title: Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblotting.
abstract: Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [11C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathology model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [11C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [11C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [11C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [11C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.
authors.affiliation: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden.
authors.forename: Xiaotian T
authors.initials: XT
authors.lastname: Fang
authors.affiliation: Department of Medicinal Chemistry, Preclinical PET Platform, Box 574, 751 23 Uppsala, Sweden; PET Centre, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Department of Medicinal Chemistry, Preclinical PET Platform, Box 574, 751 23 Uppsala, Sweden; PET Centre, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.affiliation: Department of Medicinal Chemistry, Preclinical PET Platform, Box 574, 751 23 Uppsala, Sweden; PET Centre, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Yngve
authors.affiliation: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Cato
authors.affiliation: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden.
authors.forename: Dag
authors.initials: D
authors.lastname: Sehlin
authors.affiliation: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden. Electronic address: stina.syvanen@pubcare.uu.se.
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000378:metabolism*; D015151:Immunoblotting / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010091:Oximes / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D016564:Amyloid beta-Protein Precursor; D002250:Carbon Radioisotopes; C578936:Grm5 protein, mouse; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: Alzheimer's disease; PET; [(11)C]ABP688; mGluR5