Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation.
Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation.
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DOI：
10.1523/jneurosci.4456-09.2010
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发表时间：
2010-02-17
期刊：
影响因子：
--
通讯作者：
Hyman BT
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文献类型：
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作者：
Wu HY;Hudry E;Hashimoto T;Kuchibhotla K;Rozkalne A;Fan Z;Spires-Jones T;Xie H;Arbel-Ornath M;Grosskreutz CL;Bacskai BJ;Hyman BT
在阿尔茨海默病（AD）大脑中，含有β淀粉样蛋白的斑块被营养不良的神经突包围，但斑块是否以及如何诱导这些神经炎异常仍不清楚。我们测试了以下假设：斑块周围的可溶性 Aβ 寡聚体组装体诱导钙介导的二次级联反应，导致局部神经突营养不良。我们发现可溶性 Aβ 寡聚体会导致钙依赖性磷酸酶 CaN (PP2B) 的激活，进而激活激活 T 细胞的转录因子核因子 (NFAT)。即使在没有 Aβ 的情况下，这些信号通路的激活也足以在培养物和成年小鼠大脑中的神经元中产生 Aβ 诱导的营养不良性神经突、树突简化和树突棘损失的虚拟表型。重要的是，AD 小鼠模型中 Aβ 沉积物附近的形态缺陷可通过 CaN 抑制得到改善，这支持了 CaN/NFAT 被 Aβ 异常激活的假设，并且 CaN/NFAT 激活是斑块附近神经元结构破坏的原因。与此相一致，我们还检测到 AD 患者皮质核部分中活性形式的 CaN 和 NFATc4 水平增加。因此，Aβ 似乎至少部分通过激活 CaN 和随后的 NFAT 介导的下游级联来介导 AD 的神经变性。
Amyloid beta containing plaques are surrounded by dystrophic neurites in the Alzheimer disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of Aβ, which surround plaques, induce calcium mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble Aβ oligomers lead to activation of the calcium-dependent phosphatase CaN (PP2B) which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of Aβ, is sufficient to produce a virtual phenocopy of Aβ induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of Aβ deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN/NFAT are aberrantly activated by Aβ, and that CaN/NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, Aβ appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.