title: Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.
abstract: We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Abeta deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Abeta plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Abeta pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(-) astrogliosis uncoupled with microgliosis or coupled with PBR(+) microgliosis associated with irreversible neuronal insults; and (2) PBR(+) astrogliosis coupled with PBR(- or +/-) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Sawada
authors.forename: Maiko
authors.initials: M
authors.lastname: Ono
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Motoki
authors.initials: M
authors.lastname: Inaji
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000081:Acetamides / Q000378:metabolism; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D017690:Cell Transplantation / Q000000981:diagnostic imaging / Q000379:methods; D002490:Central Nervous System / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D016627:Oxidopamine / Q000633:toxicity; D010647:Phenyl Ethers / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000081:Acetamides; D016564:Amyloid beta-Protein Precursor; C118942:DAA 1106; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D010647:Phenyl Ethers; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D016875:tau Proteins; D016627:Oxidopamine; D007608:Kainic Acid