IPSC‐derived neurons with amyloid‐β treatment reflect features of Alzheimer’s disease patients

Abstract

AbstractBackgroundThere is increasing evidence showing that induced pluripotent stem cells (iPSC)‐derived brain cells recapitulate disease‐relevant processes in patients with Alzheimer’s disease (AD). However, it remains unclear to what extent iPSC‐derived neurons treated with amyloid‐β (Aβ) reflect patient Aβ burden and other endophenotypes as determined by changes in protein expression.MethodTo investigate this, we firstly generated iPSC lines from 14 individuals with AD from the Deep and Frequent Phenotyping (DFP) pilot cohort. All of these individuals had undergone clinical measures (i.e. Mini Mental Score Examination) and neuropathological measures (i.e. Aβ, p‐tau and tau). We then differentiated these lines into cortical neurons and treated them with Aβ oligomers. We collected both cell media and cell lysates and measured over 5000 proteins in these samples using SOMAscan assay. In addition, proteins in the cerebrospinal fluid (CSF) and plasma of the same individuals were also measured using the same assay.ResultUsing Wilcox test, we identified 627 proteins that were differentially expressed in neuronal cultures under Aβ oligomers treatment after multiple correction. These proteins were significantly enriched in 14 pathways such as TGF‐β signaling pathway, Ras signaling pathway and MAPK signaling pathway etc. From protein co‐expression network analysis, we identified 12 modules (ranging from 45 to 2029 proteins) in neuronal cultures. Of them, eight were significantly associated with at least one endophenotype of the amyloid/Tau/Neurodegeneration/Cognition AT(N)C framework. We further checked the replication of these modules in human. We found that eight and nine modules were significantly preserved in CSF and plasma, respectively. Furthermore, some preserved modules were also significantly associated with some AD endophenotypes including Aβ.ConclusionThese results suggests that iPSC‐derived neurons with Aβ treatment reflect the patients’ endophenotypes, indicating that their use in capturing disease‐relevant processes in AD.