Pin1 介导 Aβ 诱导的树突棘缺失。
Pin1 mediates Aβ-induced dendritic spine loss.
机构信息
Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
出版信息
Sci Signal. 2018 Mar 20;11(522):eaap8734. doi: 10.1126/scisignal.aap8734.
Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (Aβ), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-trans prolyl isomerase Pin1 was a critical downstream target of Aβ-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to Aβ induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ-treated wild-type cells but had no effect on -null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer's disease.
早期阿尔茨海默病的特征是大脑新皮质中树突棘的丧失。这种现象先于 tau 病理学、斑块形成和神经退行性变发生，并可能导致患者的突触丧失、记忆障碍和行为改变。研究表明，树突棘丧失是由可溶性三聚体淀粉样蛋白-β (Aβ) 诱导的，Aβ 通过突触后信号转导激活蛋白磷酸酶钙调神经磷酸酶。我们研究了钙调神经磷酸酶如何引起棘突病理，并发现顺式-反式脯氨酰异构酶 Pin1 是 Aβ-钙调神经磷酸酶信号的关键下游靶标。在树突棘中，Pin1 与钙调神经磷酸酶相互作用并被其去磷酸化，这迅速抑制了其异构酶活性。Pin1 敲除或暴露于 Aβ 诱导成熟树突棘丧失，外源性 Pin1 可预防这种丧失。钙调神经磷酸酶抑制剂 FK506 可阻止 Aβ 处理的野生型细胞中的树突棘丧失，但对 Pin1-/-神经元无影响。这些数据表明 Pin1 参与了早期阿尔茨海默病中的树突棘维持和突触丧失。
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