Postdoc Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangdong, China (People's Republic)
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-beta (Aβ) plaque accumulation, tau hyperphosphorylation, neuronal loss, and neuroinflammation. Early intervention is critical for slowing disease progression, but identifying reliable early biomarkers poses a significant challenge. In this study, we developed a cerebral organoid model from human induced pluripotent stem cells (hiPSCs) derived from familial AD (FAD) patients, effectively recapitulating key AD features, including Aβ plaques, tau pathology, and neuronal apoptosis, within just 30 days.
Our organoid model exhibited significant Aβ accumulation confirmed by immunofluorescent staining techniques. Electrophysiological recordings using high-density microelectrode arrays (HD-MEA) revealed impaired neuronal activity in FAD organoids compared to control (CTRL) organoids, indicating disrupted synaptic integrity and decreased network functionality. Spatial transcriptomics analysis highlighted the upregulation of UNC5D, a gene associated with neuronal survival and microglia-independent neuroinflammation, suggesting its potential as an early biomarker for AD.
To examine the interplay between immune responses and neurodegeneration, we co-cultured FAD organoids with iPSC-derived macrophages (iMACs), which differentiated into microglia-like cells and effectively engaged with Aβ plaques. This interaction demonstrated the potential for iMACs to mitigate Aβ burden and influence the inflammatory environment within the organoids.
Our findings establish a robust platform for studying early AD mechanisms and illustrate the complex relationships between neuroinflammation and neurodegeneration. This work provides critical insights for identifying biomarkers and therapeutic targets aimed at enabling early intervention strategies, ultimately contributing to innovative approaches for slowing AD progression and enhancing neuronal resilience.
Funding Source: YY was supported by Guangzhou Postdoctoral Supporting fundings, Guangdong Postdoc researcher fundings, Huangpu Postdoc Researcher fundings and CAS Special Research Assistant fundings.
