MYELIN-DERIVED FATTY ACIDS AMELIORATE PATHOLOGY IN HUMAN CORTICAL ORGANOIDS FROM ALZHEIMER’S DISEASE

Age-related metabolic decline profoundly affects brain function, and increasing evidence indicates that myelin structure and metabolism are altered during aging. In Alzheimer’s disease (AD), where aging is the strongest risk factor, impaired myelin metabolic support may contribute to neurodegeneration. Building on our recent findings that myelin can function as an energy reservoir (Nat Metab, 2025; 10.1038/s42255-025-01244-7), we investigated whether deficits in myelin-derived metabolic substrates exacerbate AD pathology. Human cortical organoids were generated from induced pluripotent stem cells (iPSCs) derived from a female patient with sporadic AD. Organoids were validated for regional identity and maturation using neuronal and glial markers (SOX2, MAP2, TUJ1, CTIP2, S100β). Key pathological features—including oxidative stress, tau hyperphosphorylation, astrocyte reactivity, inflammatory signaling, and synaptic integrity—were assessed by immunofluorescence and RT-qPCR. Exposure of 4-month-old AD organoids to myelin-derived fatty acids significantly reduced redox-sensitive imaging signals, Nrf2-associated inflammatory responses, phospho-tau levels, and astrogliosis, while increasing the expression of functional astrocytic markers and synaptic proteins. Ongoing studies using calcium imaging and microelectrode arrays (MEAs) are evaluating the impact of these treatments on neuronal network activity. In parallel, 2D human astrocyte cultures are being used to investigate the metabolic regulation of oxidative stress and reactive phenotypes. Together, these findings suggest that myelin-derived fatty acids can mitigate AD-related pathology in human brain organoids and identify aged myelin metabolism as a critical modulator of disease progression.