iPSCs from Alzheimer’s disease patients display neuronal differentiation impairment of neural progenitor cells

Authors: Weidong Le

Published: 2020-12-07

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common age‐related dementia associated with progressive neuronal loss. However, the cause of the disease is still unknown. Induced pluripotent stem cells (iPSCs) derived from somatic cells of AD patients provide unique opportunities to model the early development of AD.ObjectiveThe objective of this study is to use iPSCs system to determine the molecular mechanisms of neuronal loss in AD.MethodsWe used iPSC lines generated from fibroblasts of two familial AD (FAD) patients with autosomal dominant mutations in presenilin 1 (PSEN1) (S169del) or (A246E). We characterized the AD‐iPSCs characteristic properties of human pluripotent stem cells and differentiate them into functional neurons.ResultWe found abnormally enhanced neuronal differentiation in AD iPSC‐derived neural progenitor cells (AD‐NPCs), and a reduction in the number of NPCs in AD‐NPCs during differentiation. Consistently, we detected a decreased proliferation and an increased apoptosis in differentiating AD‐NPCs. In addition, we identified the same phenotypes when PSEN1 with the mutation of A246E was introduced into control iPSCs. Furthermore, knockdown of mutated PSEN1 in AD‐NPCs significantly attenuated the premature neuronal differentiation. Our results suggest that PSEN1 mutation causes reduction in the NPC pool, which might be relevant to the neuronal loss in the brain of AD patients. Additionally, our genome‐wide transcript analyses identified differentially expressed genes relevant to neuronal differentiation and cell cycle in differentiating AD‐NPCs.ConclusionCollectively, our study uncovers previously unappreciated early NPC dysfunctions in FAD‐NPCs and provides new cues to elucidate molecular mechanisms underlying AD development.