TARGETING ASTROCYTE REACTIVITY TO BETA-AMYLOID PREVENTS OLIGODENDROCYTE MATURATION IMPAIRMENT: NEUROPROTECTIVE POTENTIAL OF CO-ULTRAPEA/LUTEOLIN

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects grey matter and also involves white matter alterations associated with cognitive decline. Myelin is produced by oligodendrocytes (OLs), the neuroglial cells whose maturation is strongly influenced by astrocytes. However, the mechanisms underlying astrocyte-oligodendrocyte crosstalk in AD remain poorly understood.
This study aimed to investigate the role of astrocytes in the maturation of oligodendrocyte precursor cells (OPCs) following beta-amyloid 1-42 (Aβ_1-42) exposure and to evaluate the therapeutic potential of co-ultramicronized palmitoylethanolamide/luteolin (co-ultraPEA/Lut), a formulation with established anti-inflammatory and neuroprotective properties.
Primary OPCs and astrocytes were isolated from rat pups (PND 0–2). Two experimental paradigms were used:
1.Direct treatment of OPCs with 1µM Aβ_1-42 with or without 3µM co-ultraPEA/Lut;
2.Treatment of OPCs with astrocyte-conditioned medium (ACM) from astrocytes pre-exposed to 1µM Aβ_1-42 with or without 3µM co-ultraPEA/Lut.
Immunofluorescence and western blotting (WB) experiments were performed on OLs and astrocytes.
Notably, our data showed that Aβ_1-42 induced a reduction in the number and complexity of mature OLs only in the ACM condition (paradigm 2). WB analysis of ACM-treated OPCs revealed altered expression of myelin basic protein (MBP) and monocarboxylate transporter 1 (MCT1), both critical for myelination. Interestingly, co-ultraPEA/Lut treatment prevented the alterations observed in the ACM condition.
Our findings suggest that astrocyte reactivity to Aβ_1-42 alters oligodendrocyte maturation and morphology, highlighting the central role of astrocytes in OL development. These results underscore the importance of glial cell interactions in AD and support further investigation of co-ultraPEA/Lut as a potential therapeutic strategy.