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Knockdown Gene Expression Profile of potential key drivers for Alzheimer’s Disease in human iPSC-derived neurons.

ABSTRACT: In this study, we construct network models by integrating multi-omics data in ROSMAP and MAYO cohort in AMP-AD consortium and infer 19 potential key drivers for Alzheimer’s Disease and related dementia (ADRD). To validate these 19 targets in modulating AD-related pathology (Amyloid-beta and phosphorylated-Tau) and investigating the biological functions and pathways they regulate, we performed RNAi-based knockdown of 19 targets inferred by computational systems biology model in human iPSC-derived neurons (iNs) and measured gene expression profile for each knockdown by RNAseq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228156 | GEO | 2023/04/01

REPOSITORIES: GEO

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Project description:Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer’s disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the (FosB proto-oncogene) FOSB and (ERCC excision repair 1) ERCC1 genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.

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Knockdown Gene Expression Profile of potential key drivers for Alzheimer’s Disease in human iPSC-derived neurons.

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