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

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 im...

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Veröffentlicht in:	Free radical biology & medicine Jg. 240; S. 641 - 649
Hauptverfasser:	Trostchansky, A., Alarcón, M.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Inc 01.12.2025
Schlagworte:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Amyloid-β Arachidonate 12-Lipoxygenase - genetics Arachidonate 12-Lipoxygenase - metabolism Blood Platelets - enzymology Blood Platelets - metabolism Cerebral Amyloid Angiopathy - genetics Cerebral Amyloid Angiopathy - metabolism Cerebral Amyloid Angiopathy - pathology Cyclooxygenase Cyclooxygenase 1 - genetics Cyclooxygenase 1 - metabolism Humans Lipoxygenase Peptide Fragments - metabolism Platelet Activation Platelets rhoA GTP-Binding Protein - genetics rhoA GTP-Binding Protein - metabolism Signal Transduction Cyclooxygenase Amyloid-β Lipoxygenase Platelets
ISSN:	0891-5849, 1873-4596, 1873-4596
Online-Zugang:	Volltext
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Zusammenfassung:	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. [Display omitted] •Novel PTGS1–ALOX12–RhoA pathway regulates amyloid-β40 release from activated platelets.•Platelets are key sources of Aβ40, amplifying cerebral amyloid angiopathy and Alzheimer’s disease pathology.•Targeting the platelet COX/LOX–RhoA axis may reduce vascular amyloid deposition and slow. neurodegenerative progression.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0891-5849 1873-4596 1873-4596
DOI:	10.1016/j.freeradbiomed.2025.08.060