D-084 | RNAseq analysis of patient-induced pluripotent stem cells-derived cortical neurons uncovers commonly dysregulated genes in familial Alzheimer’s disease.

Disorders of the Nervous System
Author: Luciana Isaja | Email: lucianaisaja@gmail.com

Luciana Isaja^1°, Mercedes Vautier^1°, Sofía Mucci^1°,  Soledad Rodríguez Varela^1°, Giulia Clas^1°, Diego García Chialva^1°, María Elida Scassa^1°,  Gustavo Emilio Sevlever^1°, Ezequiel Ignacio Surace^1°, Leonardo Romorini^1°

^1° Instituto de Neurociencias (FLENI-CONICET)

Autosomal dominant Alzheimer’s disease (AD) is mainly caused by pathogenic variants in three genes: amyloid precursor protein, presenilin 1 and 2 (PSEN1-2). We previously demonstrated that cortical neurons derived from the human induced pluripotent stem cells (hiPSCs) line FFAD1 carrying the PSEN1 p.T119I variant exhibited AD pathological features (e.g. increased Tau phosphorylation at Thr231) compared to PSEN1 WT hiPSCs (UOW002iA)-derived neurons. Here, we performed an RNA-Seq assay to analyze differences between the transcriptome of cortical neurons derived from both FFAD1 and UOW002iA lines. We identified 85 differentially expressed (DE) genes: 34 downregulated and 51 upregulated. Gene ontology analysis revealed significant enrichment in genes associated with cellular homeostasis, substance transport and iron homeostasis. We validated 13 DE by RT-qPCR, confirming decreased ACP5, ICAM4, NOS3, TUBA4A, TMEM87B, HSPA6 and increased PROKR2, RGDP2, ADAMTS15, THSD1, TRP6, GPD1 and GRIN2A mRNA expression levels in FFAD1-derived neurons. Additionally, by RT-qPCR, we determined that in cortical neurons derived from hiPSCs harboring the PSEN1 p.A246E variant, TUBA4A, NOS3, ACP5, TRPC6, THSD1, GPD1 and PROKR2 mRNA expression levels showed the same expression trends as observed in FFAD1 derived-neurons when compared to PSEN1 WT derived-neurons. These results might provide valuable insights into common pathways driving disease progression in hereditary AD.