Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling.
Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling.
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DOI：
10.1523/jneurosci.1064-09.2009
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发表时间：
2009-10-14
期刊：
影响因子：
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通讯作者：
Norris CM
中科院分区：
文献类型：
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作者：
Abdul HM;Sama MA;Furman JL;Mathis DM;Beckett TL;Weidner AM;Patel ES;Baig I;Murphy MP;LeVine H 3rd;Kraner SD;Norris CM
在被钙调磷酸酶激活后，活化T细胞的核因子（NFAT）易位到细胞核并指导参与炎症和Ca 2+失调的许多分子的转录，这两者都是阿尔茨海默病（AD）的突出特征。然而，AD中的NFAT信号传导仍然相对未被研究。使用分离的细胞质和核组分制备的快速尸检死后人脑组织，我们表明，NFAT 1和3转移到核隔室在海马在不同阶段的神经病理学和认知能力下降，而NFAT 2保持不变。NFAT 1在轻度认知障碍（MCI）受试者中表现出与孤立核分数更大的相关性，而NFAT 3在重度痴呆和AD受试者中表现出强烈的核偏倚。与NFAT 1类似，钙调神经磷酸酶-A α在认知能力下降的早期阶段也表现出核偏向性。但是，与NFAT 1不同，与NFAT 3相似，随着认知能力的恶化，钙调神经磷酸酶的核偏好变得更加明显。钙调神经磷酸酶/NFAT 3的变化与死后海马中可溶性Aβ（1-42）水平直接相关，特别是寡聚Aβ，强烈刺激原代大鼠星形胶质细胞培养物中的NFAT活化。寡聚体Aβ还导致星形胶质细胞培养物中兴奋性氨基酸转运蛋白2（EAAT 2）蛋白水平显著降低，这可被NFAT抑制剂阻断。此外，在混合培养物中抑制星形胶质细胞NFAT活性可改善Aβ依赖性谷氨酸升高和神经元死亡。结果表明，NFAT信号在AD中选择性改变，并且可能在驱动Aβ介导的神经变性中起重要作用。
Upon activation by calcineurin, the nuclear factor of activated T cells (NFAT) translocates to the nucleus and guides the transcription of numerous molecules involved in inflammation and Ca2+ dysregulation, both of which are prominent features of Alzheimer’s disease (AD). However, NFAT signaling in AD remains relatively uninvestigated. Using isolated cytosolic and nuclear fractions prepared from rapid-autopsy postmortem human brain tissue, we show that NFATs 1 and 3 shifted to nuclear compartments in the hippocampus at different stages of neuropathology and cognitive decline, while NFAT2 remained unchanged. NFAT1 exhibited greater association with isolated nuclear fractions in subjects with mild cognitive impairment (MCI), while NFAT3 showed a strong nuclear bias in subjects with severe dementia and AD. Similar to NFAT1, calcineurin-Aα also exhibited a nuclear bias in the early stages of cognitive decline. But, unlike NFAT1 and similar to NFAT3, the nuclear bias for calcineurin became more pronounced as cognition worsened. Changes in calcineurin/NFAT3 were directly correlated to soluble Aβ(1-42) levels in postmortem hippocampus, and oligomeric Aβ, in particular, robustly stimulated NFAT activation in primary rat astrocyte cultures. Oligomeric Aβ also caused a significant reduction in excitatory amino acid transporter 2 (EAAT2) protein levels in astrocyte cultures, which was blocked by NFAT inhibition. Moreover, inhibition of astrocytic NFAT activity in mixed cultures ameliorated Aβ-dependent elevations in glutamate and neuronal death. The results suggest that NFAT signaling is selectively altered in AD and may play an important role in driving Aβ-mediated neurodegeneration.