Platelet COX and LOX enzymes orchestrate amyloid-β secretion via RhoA signaling: Implications for neurodegenerative diseases

Abstract

Arachidonic acid metabolism through cyclooxygenase (COX) and lipoxygenase (LOX) pathways is fundamental to inflammation, vascular homeostasis, and neuronal signaling. Here, we investigated the roles of platelet-expressed COX (PTGS1) and LOX (ALOX12) isoforms in amyloid-β (Aβ) secretion, a process implicated in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Using an integrative approach combining bioinformatic protein–protein interaction mapping, pathway enrichment analysis, and experimental validation, we identified extensive networks linking PTGS and ALOX isoforms to cytoskeletal remodeling, mitochondrial function, and vesicle trafficking. Functional enrichment pointed to key roles for PTGS1 and ALOX12 in platelet activation and secretory processes. In vitro studies demonstrated that stimulation of human platelets with TRAP-6 triggered a robust increase in Aβ40 secretion, which was significantly attenuated by COX inhibition or blockade of RhoA, a critical regulator of cytoskeletal dynamics. These findings suggest that platelet-derived Aβ release is driven by COX/LOX-dependent signaling via RhoA. While our results support a COX/LOX-RhoA axis, we recognize that causality remains to be fully established, and the role of ALOX12 requires further experimental validation. Given the vascular deposition of Aβ40 in CAA, our results position platelets as important peripheral contributors to neurovascular amyloidosis. This study should therefore be viewed as hypothesis-generating, underscoring the therapeutic potential of targeting platelet signaling pathways to mitigate Aβ-driven vascular pathology.