Gliosis und Neurogenese - neue Ansätze zur regenerativen Therapie im Alzheimer Maus Modell

神经胶质增生和神经发生——阿尔茨海默病小鼠模型再生治疗的新方法

• 批准号: 35326022
• 负责人: Professorin Dr. Magdalena Götz
• 金额: --
• 依托单位: Institut für Physiologische Genomik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/35326022?language=en
• 关键词: Gliosis; und; Neurogenese; neue; Ans

Although neurogenesis persists in restricted regions of the adult mammalian brain such as the subpendymal zone in the lateral wall of the lateral ventricle or the hippocampal subgranular layer, endogenous replacement of neurons does not take place after brain injury in all other brain regions where neurogenesis does not occur into adulthood. However, recently major progress has been made in the attempt to reinstruct neurogenesis after brain injury in the cerebral cortex, an area devoid of adult neurogenesis. Our previous work has identified the transcription factors Olig2 and Pax6 as respectively key anti-neurogenic and pro-neurogenic signals of adult subependymal precursors (Hack et al., 2005). Consistent with its anti-neurogenic function, we found that a strong induction of Olig2 was a common hallmark of both acute (stab-wound) and chronic (cerebral amyloidosis) injuries, while no neurogenic factors were upregulated (Buffo et al., 2005). More importantly, blockade of Olig2 function led to Pax6-upregulation after stabwound injury and resulted in the generation of new neurons from proliferating glial cells in the cerebral cortex (Buffo et al., 2005).We now would like to expand this approach towards neuronal regeneration to mouse models of neurodegenerative lesions. We discovered previously that the gliotic reaction differs profoundly between a model of cerebral amyloidosis and acute injury in regard to the type of glial cells activating Olig2 and their lack of cell proliferation (Buffo et al., 2005). To examine whether the NG2-positive glial cells specifically reacting to amyloidosis can also be instructed towards neurogenesis in vivo we will employ cell type-specific targeting of pseudotyped viral vectors. We have shown that lentiviral vectors with the Mokola pseudotype infect predominantly NG2-positive glial cells that are particularly prominent in the model of cerebral amyloidosis. Conversely, lentiviral vectors with the LMCV pseudotype infect selectively astrocytes in vivo. These viral vectors will be applied to manipulate Olig2 function by the use of dominant-negative constructs or inducing Pax6 or Ngn2 expression in the specific subset of glial cells in the adult cortex of mouse strains showing early amyloidosis or recapitulating all the pathological hallmarks of the Alzheimer disease, including neuronal loss. These experiments will clarify whether the very same molecular machinery that triggers neurogenesis in acute injuries can also instruct endogenous neuronal replacement in the distinct glial subtypes reacting to amyloidosis in chronic neurodegeneration models. Moreover, the viral lineage tracing will further allow us to determine the potential and progeny of distinct types of glial cells in different injuryparadigms.

尽管神经发生持续存在于成年哺乳动物大脑的有限区域，例如侧脑室侧壁的室管膜下区或海马颗粒下层，但在所有其他不发生神经发生的大脑区域，脑损伤后不会发生神经元的内源性替代。发生到成年期。然而，最近在大脑皮层（缺乏成人神经发生的区域）脑损伤后重建神经发生的尝试方面取得了重大进展。我们之前的工作已确定转录因子 Olig2 和 Pax6 分别是成人室管膜下前体的关键抗神经源性和促神经源性信号（Hack 等，2005）。与其抗神经源性功能一致，我们发现 Olig2 的强烈诱导是急性（刺伤）和慢性（脑淀粉样变性）损伤的共同标志，而没有神经源性因子上调（Buffo 等人，2005） 。更重要的是，Olig2 功能的阻断导致刺伤后 Pax6 上调，并导致大脑皮层中增殖的神经胶质细胞产生新的神经元（Buffo 等人，2005）。我们现在希望将这种方法扩展到神经元神经退行性病变小鼠模型的再生。我们之前发现，脑淀粉样变性模型和急性损伤模型之间的神经胶质细胞反应在激活 Olig2 的神经胶质细胞类型及其缺乏细胞增殖方面存在显着差异（Buffo 等人，2005）。为了检查对淀粉样变性特异性反应的 NG2 阳性神经胶质细胞是否也可以在体内指导神经发生，我们将采用假型病毒载体的细胞类型特异性靶向。我们已经证明，具有 Mokola 假型的慢病毒载体主要感染 NG2 阳性神经胶质细胞，这些细胞在脑淀粉样变性模型中尤其突出。相反，具有 LMCV 假型的慢病毒载体选择性地感染体内星形胶质细胞。这些病毒载体将用于通过使用显性失活构建体或在显示早期淀粉样变性或重现阿尔茨海默病所有病理特征的小鼠品系成年皮质中的特定神经胶质细胞亚群中诱导 Pax6 或 Ngn2 表达来操纵 Olig2 功能疾病，包括神经元损失。这些实验将阐明在急性损伤中触发神经发生的相同分子机制是否也可以指导慢性神经变性模型中对淀粉样变性反应的不同神经胶质亚型中的内源性神经元替代。此外，病毒谱系追踪将进一步使我们能够确定不同类型的神经胶质细胞在不同损伤范式中的潜力和后代。