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 (Aβ₄₂), 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 Aβ₄₂-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 Aβ₄₂ induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ₄₂-treated wild-type cells but had no effect on Pin1-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缺失。这种现象先于 tau 病理、斑块形成和神经变性，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，树突棘丢失是由可溶性多聚淀粉样蛋白-β (Aβ ₄₂ ) 诱导的，它通过突触后信号转导激活蛋白磷酸酶钙调神经磷酸酶。我们调查了钙调神经磷酸酶如何引起脊柱病变，发现顺反式脯氨酰异构酶 Pin1 是 Aβ _{42的关键下游靶标}-钙调神经磷酸信号。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，从而迅速抑制其异构酶活性。敲除 Pin1 或暴露于 Aβ ₄₂会导致成熟树突棘的丢失，而外源性 Pin1 可阻止这种情况发生。_{钙调神经磷酸酶抑制剂 FK506 阻止了 Aβ 42}处理的野生型细胞中的树突棘丢失，但对Pin1无效神经元没有影响。这些数据表明 Pin1 与早期阿尔茨海默病的树突棘维持和突触丢失有关。