Uncorrected Author Proof Journal of Alzheimer’s Disease xx (2022) x–xx DOI 10.3233/JAD-220320 IOS Press 1 Urokinase-Type Plasminogen Activator Triggers Wingless/Int1-Independent Phosphorylation of the Low-Density Lipoprotein Receptor-Related Protein-6 in Cerebral Cortical Neurons 1 2 3 4 5 Ariel Diaz a , Cynthia Martin-Jimenez a , Yena Woo a , Paola Merino a , Enrique Torre a and Manuel Yepes a,b,c,∗ 6 7 a Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA, USA 8 9 b Department of Neurology, Emory University, Atlanta, GA, USA 10 c Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA, USA 11 Accepted 12 July 2022 12 Pre-press 9 August 2022 13 Abstract. 14 Background: 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)--catenin pathway plays a central role in the pathogenesis of AD. Soluble amyloid- (A) prevents the phosphorylation of the low-density lipoprotein receptor-related protein-6 (LRP6), and the resultant inactivation of the Wnt--catenin pathway prompts the amyloidogenic processing of the amyloid- protein precursor (APP) and causes synaptic loss. 15 16 17 18 19 20 21 Objective: To study the role of neuronal uPA in the pathogenesis of AD. 22 Methods: 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). 23 24 Results: We show that uPA activates the Wnt--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--catenin pathway protects the synapse from the harmful effects of soluble A and prevents the amyloidogenic processing of APP by inhibiting the expression of -secretase 1 (BACE1) and the ensuing generation of A 40 and A 42 peptides. 25 26 27 28 29 Conclusion: uPA protects the synapse and antagonizes the inhibitory effect of soluble A on the Wnt--catenin pathway by providing an alternative pathway for LRP6 phosphorylation and -catenin stabilization. 30 31 Keywords: Amyloid- protein precursor secretases, -Catenin, plasmin, urokinase-type plasminogen activator 32 ∗ Correspondence to: Manuel Yepes, Division of Neurophar- macology and Neurologic Diseases, Yerkes National Primate Research Center, 954 Gatewood Road-NE, Atlanta, GA 30329- 4208, USA. Tel.: +1 404 727 6468; Fax: +1 404 727 8070; E-mail: myepes@emory.edu. ISSN 1387-2877 © 2022 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).