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The Journal of Neuroscience, November 19, 2008, 28(47):12255-12267; doi:10.1523/JNEUROSCI.2312-08.2008
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Neurobiology of Disease
Imaging of Peripheral Benzodiazepine Receptor Expression as Biomarkers of Detrimental versus Beneficial Glial Responses in Mouse Models of Alzheimer's and Other CNS Pathologies
Bin Ji,1 Jun Maeda,1 Makoto Sawada,2 Maiko Ono,1 Takashi Okauchi,1 Motoki Inaji,1 Ming-Rong Zhang,1 Kazutoshi Suzuki,1 Kiyoshi Ando,1,3 Matthias Staufenbiel,4 John Q. Trojanowski,5 Virginia M. Y. Lee,5 Makoto Higuchi,1 andTetsuya Suhara1 1Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan, 2Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601, Japan, 3Nonhuman Primate Laboratory, Central Institute for Experimental Animals, Kawasaki, Kanagawa 216-0001, Japan, 4Novartis Institutes for Biomedical Research–Basel, CH-4002 Basel, Switzerland, and 5Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Correspondence should be addressed to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: mhiguchi{at}nirs.go.jp
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 Aβ 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 Aβ plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Aβ 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.
Key words: neurodegenerative disorders; microglia; astrocyte; peripheral benzodiazepine receptor; glial cell line-derived neurotrophic factor; Alzheimer's disease
Received May 21, 2008; revised July 15, 2008; accepted Oct. 5, 2008.
Correspondence should be addressed to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Email: mhiguchi{at}nirs.go.jp
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[Abstract] [Full Text] [PDF]
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