Remyelination Under Alzheimer's Disease: Morphological and GO Analysis in human iPSC-Derived OPCs and tissue

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, tau neurofibrillary tangles, progressive white matter degeneration, and impaired. Oligodendrocyte precursor cells (OPCs), which are essential for myelin repair, exhibit functional deficits in AD. This study investigated the relationship between AD pathology and OPC dysfunction and evaluated the therapeutic potential of the phosphodiesterase 4D (PDE4D) inhibitor RICE01 to restore morphological OPCs. Post-mortem human AD brain tissue and human iPSC-derived OPCs exposed to Aβ were analyzed, alongside transcriptomic and phosphoproteomic data. Areas surrounding Aβ plaques showed increased degraded myelin basic protein (MBP) and loss of intact MBP. Newly formed oligodendrocytes were enriched near Aβ plaques and tau, indicating an active but insufficient remyelination response. In vitro, Aβ exposure reduced OPC surface area, whereas RICE01 restored this. Enrichment analyses of OPCs and neurons identified Aβ-associated alterations in pathways related to cytoskeletal organization, extracellular matrix regulation, and inflammation. RICE01 upregulated several of these functions, suggesting a potential restorative effect on cells. Together, these findings demonstrate that AD pathology disrupts OPC integrity and remyelination capacity. PDE4D inhibition restores oligodendrocyte morphology and modulates signaling pathways associated with repair, highlighting PDE4D as a promising therapeutic target for preserving white matter integrity in AD.