APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer’s disease

Abstract

Background: The epsilon 4 allele of apolipoprotein E (APOE epsilon 4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE epsilon 4 accelerates amyloid-beta (A beta) deposition during the seeding stage of amyloid development in AD patient neurons. Methods: AD patient induced neurons (iNs) with an APOE epsilon 4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE epsilon 4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE epsilon 4-mediated amyloidosis. Results: We optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE epsilon 4. Remarkably, we demonstrated that A beta pathology was aggravated by the induction of APOE epsilon 4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE epsilon 4-associated AD. Conclusions: Our findings suggest that the presence of APOE epsilon 4 at the early A beta-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE epsilon 4 expression for the progression and pathogenesis of sporadic AD.