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Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.

Ji, Bin and Maeda, Jun and Sawada, Makoto and Ono, Maiko and Okauchi, Takashi and Inaji, Motoki and Zhang, Ming-Rong and Suzuki, Kazutoshi and Ando, Kiyoshi and Staufenbiel, Matthias and Trojanowski, John Q and Lee, Virginia M Y and Higuchi, Makoto and Suhara, Tetsuya (2008) Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies. The Journal of Neuroscience: the official journal of the Society for Neuroscience, 28 (47). pp. 12255-12267. ISSN 1529-2401

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.

Item Type: Article
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Keywords: neurodegenerative disorders; microglia; astrocyte; peripheral benzodiazepine receptor; glial cell line-derived neurotrophic factor; Alzheimer's disease
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:56
URI: https://oak.novartis.com/id/eprint/1334

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