Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning
Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning
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DOI：
10.1111/j.0953-816x.2004.03439.x
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Granholm, AC
中科院分区：
文献类型：
--
作者：
Hunter, CL;Quintero, EM;Granholm, AC
阿尔茨海默病的两个突出特征是基底前脑胆碱能变性和神经炎症，其特征是胶质细胞激活和促炎细胞因子的释放。Mu p75-Saporin(SAP)是一种新的免疫毒素，可模拟小鼠基底前脑胆碱能神经元的选择性丢失并导致认知功能障碍。我们报告了静脉注射后内侧隔核和腹侧斜角带胆碱能细胞的丢失。注射mup75-SAP伴随着基底前脑区小胶质细胞和星形胶质细胞的同时激活以及显著的记忆丧失。米诺环素是一种第二代四环素，具有已知的抗炎和神经保护特性，与神经胶质细胞在阿尔茨海默病病理中的作用一致，它可以减轻MU p75-SAP诱导的胆碱能细胞损失、胶质激活和下游促炎介质的转录。除了神经保护外，米诺环素治疗还减轻了似乎是mup75-SAP损害的功能性后果的认知损害。目前的研究表明，胶质相关炎症在mup75-SAP的选择性神经毒性中起着重要作用，并提示米诺环素可能为退化的胆碱能系统提供一种可行的治疗选择。
Two prominent characteristics of Alzheimer's disease are basal forebrain cholinergic degeneration and neuroinflammation characterized by glial activation and the release of pro-inflammatory cytokines. Mu p75- saporin (SAP) is a novel immunotoxin that mimics the selective loss of basal forebrain cholinergic neurons and induces cognitive impairment in mice. We report that cholinergic cell loss in the medial septal nucleus and ventral diagonal band after i.c.v. injection of mu p75-SAP is accompanied by simultaneous activation of microglia and astrocytes in the basal forebrain region as well as significant memory loss. Consistent with a role of glial cells in the pathology of Alzheimer's disease, minocycline, a second-generation tetracycline with known anti-inflammatory and neuroprotective properties, attenuated mu p75-SAP-induced cholinergic cell loss, glial activation and transcription of downstream pro-inflammatory mediators. In addition to neuroprotection, minocycline treatment mitigated the cognitive impairment that appears to be a functional consequence of mu p75-SAP lesioning. The current study demonstrates that glial-related inflammation plays a significant role in the selective neurotoxicity of mu p75-SAP, and suggests that minocycline may provide a viable therapeutic option for degenerating cholinergic systems.