Joseph Balducci

Helios Scholar

In vitro human cellular models are essential to investigate Alzheimer’s disease (AD) pathophysiology and facilitate treatment development. In this study, we used forebrain patterned neuronal organoids (FPNOs) treated with human serum to develop and characterize AD organoid models. Total-tau immunofluorescence of D90 organoids revealed AD pathology. Differential expression analysis of treated versus untreated organoids revealed a total of 4,986 significantly  differentially expressed genes (DEGs) (p-adj < 0.05). Synaptic membrane genes, typically underexpressed in AD, were overexpressed (p-adj = 2.2E-27). Excitatory neuronal genes (Ex) were upregulated (p-adj = 2.0E-10), while astrocyte genes (Ast) were downregulated (p-adj = 3.4E-13). Finally, organoid RNA signatures showed opposite patterns compared with human AD post-mortem brains. When comparing D102 versus D90 organoids, we detected 1,084 DEGs. Unlike in the first comparison, genes associated with synaptic membranes were underexpressed (p-adj = 3.3E-07). Furthermore, Ast were upregulated (p-adj = 5.55E-10) while Ex were downregulated (p-adj = 1.1E-05). Transcriptomic profiles obtained from this comparison were concordant with post-mortem human brain AD profiles. These results suggest that treatment has time-dependent effects in the AD brain organoid serum model. As results are preliminary, they need to be validated in a larger sample size and by treating organoids with AD patient serum.