Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons
Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons
复制标题
DOI：
10.1038/mp.2008.105
复制
发表时间：
2009-02-01
影响因子：
11
通讯作者：
Aiso, S.
中科院分区：
文献类型：
--
作者：
Chiba, T.;Yamada, M.;Aiso, S.
颅内可溶性淀粉样蛋白- β (A β)水平升高与阿尔茨海默病（AD）的发病机制有关。然而，导致阿尔茨海默病患者记忆丧失的神经元细胞内事件仍然难以捉摸。Humanin （HN）是一种消除Ab神经毒性的短肽。最近，我们发现HN衍生物可以激活Janus激酶2 (JAK2)/信号转换器和转录3激活器（STAT3）信号轴。我们在这里报道了一种名为colivelin的HN衍生物通过激活JAK2/STAT3轴完全恢复AD模型（Tg2576）的认知功能。因此，使用针对磷酸-(p-) STAT3的特异性抗体进行免疫荧光染色显示，阿尔茨海默病模型小鼠和阿尔茨海默病患者海马神经元中p-STAT3水平均呈年龄依赖性下降。在Tg2576小鼠中，A β 1-42脑室内给药可下调p-STAT3，而抗A β抗体被动免疫则相反地恢复海马p-STAT3水平，与脑Ab负荷的减少平行。β 1-42在初级神经元中持续调节p-STAT3水平。药理抑制JAK2/STAT3轴不仅通过下调乙酰胆碱生成酶胆碱乙酰转移酶导致空间工作记忆的显著丧失，而且还使m1型毒蕈碱乙酰胆碱受体脱敏。因此，我们提出了一种新的理论来解释与AD相关的记忆障碍：JAK2/STAT3轴的β依赖性失活通过胆碱能功能障碍导致记忆丧失。我们的发现不仅为阿尔茨海默病提供了一个新的病理标志，也为阿尔茨海默病的治疗提供了一个新的靶点。
Elevation of intracranial soluble amyloid-beta (A beta) levels has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular events in neurons, which lead to memory loss in AD, however, remain elusive. Humanin (HN) is a short neuroprotective peptide abolishing Ab neurotoxicity. Recently, we found that HN derivatives activate the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. We here report that an HN derivative named colivelin completely restored cognitive function in an AD model (Tg2576) by activating the JAK2/STAT3 axis. In accordance, immunofluorescence staining using a specific antibody against phospho-(p-) STAT3 revealed that p-STAT3 levels in hippocampal neurons age-dependently decreased in both AD model mice and AD patients. Intracerebroventricular administration of A beta 1-42 downregulated p-STAT3 whereas passive immunization with anti-A beta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Ab burden. A beta 1-42 consistently modulated p-STAT3 levels in primary neurons. Pharmacological inhibition of the JAK2/STAT3 axis not only induced significant loss of spatial working memory by downregulating an acetylcholine-producing enzyme choline acetyltransferase but also desensitized the M1-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: A beta-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in AD but also a novel target in AD therapy.