Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.
Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.
复制标题
DOI：
10.1523/jneurosci.2312-08.2008
复制
发表时间：
2008-11-19
期刊：
影响因子：
--
通讯作者：
Suhara T
中科院分区：
文献类型：
--
作者：
Ji B;Maeda J;Sawada M;Ono M;Okauchi T;Inaji M;Zhang MR;Suzuki K;Ando K;Staufenbiel M;Trojanowski JQ;Lee VM;Higuchi M;Suhara T
我们证明了外周苯二氮卓受体（PBR）成像在阿尔茨海默病（AD）的活体小鼠模型中作为神经胶质激活的生物标志物和功能特征的重要性。通过放射化学和免疫化学分析AD的两种病理标志的小鼠模型，我们发现AD样Aβ沉积与星形胶质细胞主导的PBR表达同时发生，与AD样磷酸化tau积累中的非星形胶质细胞PBR上调形成鲜明对比。由于在这些模型中tau诱导的大量神经元丢失与Aβ斑块相关的边缘神经变性不同，PBR的细胞定位分别反映了对tau和Aβ病理的有害和有益胶质反应。随后在各种非AD神经病理学模型中检查了这一概念，揭示了以下反应性胶质动力学，这些动力学是PBR差异上调的基础：（1）PBR（−）星形胶质细胞增生与小胶质细胞增生不偶联或与PBR（+）小胶质细胞增生偶联，与不可逆的神经元损伤相关;（2）PBR（+）星形胶质细胞增生与PBR（−或±）小胶质细胞增生偶联，与最小或可逆的神经元毒性相关。小胶质细胞的颅内移植也表明无毒的小胶质细胞驱动星形胶质细胞PBR表达。此外，星形胶质细胞中胶质细胞系源性神经营养因子（GDNF）的水平与星形胶质细胞PBR相关，除了在AD样tau病理模型中PBR（-）星形胶质细胞中GDNF增加，从而表明星形胶质细胞中PBR上调是神经营养支持的指标。总之，星形胶质细胞和小胶质细胞中的PBR表达分别反映了包括AD在内的多种神经退行性疾病中的有益和有害的胶质反应，这表明PBR成像在监测胶质增生对AD发病机制和治疗的影响方面具有新的应用。
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.