Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA, USA.
Department of Neurology, Emory University, Atlanta, GA, USA.
J Alzheimers Dis. 2022;89(3):877-891. doi: 10.3233/JAD-220320.
Urokinase-type plasminogen activator (uPA) is a serine proteinase found in excitatory synapses located in the II/III and V cortical layers. The synaptic release of uPA promotes the formation of synaptic contacts and the repair of synapses damaged by various forms of injury, and its abundance is decreased in the synapse of Alzheimer's disease (AD) patients. Inactivation of the Wingless/Int1 (Wnt)-β-catenin pathway plays a central role in the pathogenesis of AD. Soluble amyloid-β (Aβ) prevents the phosphorylation of the low-density lipoprotein receptor-related protein-6 (LRP6), and the resultant inactivation of the Wnt-β-catenin pathway prompts the amyloidogenic processing of the amyloid-β protein precursor (AβPP) and causes synaptic loss.
To study the role of neuronal uPA in the pathogenesis of AD.
We used in vitro cultures of murine cerebral cortical neurons, a murine neuroblastoma cell line transfected with the APP-695 Swedish mutation (N2asw), and mice deficient on either plasminogen, or uPA, or its receptor (uPAR).
We show that uPA activates the Wnt-β-catenin pathway in cerebral cortical neurons by triggering the phosphorylation of LRP6 via a plasmin-independent mechanism that does not require binding of Wnt ligands (Wnts). Our data indicate that uPA-induced activation of the Wnt-β-catenin pathway protects the synapse from the harmful effects of soluble Aβ and prevents the amyloidogenic processing of AβPP by inhibiting the expression of β-secretase 1 (BACE1) and the ensuing generation of Aβ40 and Aβ42 peptides.
uPA protects the synapse and antagonizes the inhibitory effect of soluble Aβ on the Wnt-β-catenin pathway by providing an alternative pathway for LRP6 phosphorylation and β-catenin stabilization.
尿激酶型纤溶酶原激活物（uPA）是一种丝氨酸蛋白酶，存在于位于 II/III 和 V 皮质层的兴奋性突触中。uPA 的突触释放促进了突触接触的形成和因各种形式损伤而受损的突触的修复，而在阿尔茨海默病（AD）患者的突触中其丰度降低。Wingless/Int1（Wnt）-β-连环蛋白途径的失活在 AD 的发病机制中起核心作用。可溶性淀粉样β（Aβ）可防止低密度脂蛋白受体相关蛋白-6（LRP6）的磷酸化，而 Wnt-β-连环蛋白途径的这种失活促使淀粉样β蛋白前体（AβPP）的淀粉样形成过程，并导致突触丧失。
研究神经元 uPA 在 AD 发病机制中的作用。
我们使用体外培养的鼠大脑皮质神经元、转染 APP-695 瑞典突变（N2asw）的鼠神经母细胞瘤细胞系以及纤溶酶原、uPA 或其受体（uPAR）缺失的小鼠。
我们表明 uPA 通过触发 LRP6 的磷酸化，在大脑皮质神经元中激活 Wnt-β-连环蛋白途径，这是一种不依赖于纤溶酶的机制，不需要 Wnt 配体（Wnts）的结合。我们的数据表明，uPA 诱导的 Wnt-β-连环蛋白途径的激活可保护突触免受可溶性 Aβ 的有害影响，并通过抑制β-分泌酶 1（BACE1）的表达和随后产生的 Aβ40 和 Aβ42 肽来防止 AβPP 的淀粉样形成过程。
uPA 通过提供 LRP6 磷酸化和β-连环蛋白稳定的替代途径来保护突触并拮抗可溶性 Aβ 对 Wnt-β-连环蛋白途径的抑制作用。
