Author:
Rowland Helen A.,Miller Georgina,Liu Qiang,Sharp Nicola,Ng Bryan,Wei Tina,Arunasalam Kanisa,Koychev Ivan,Hedegaard Anne,Ribe Elena M.,Chan Dennis,Chessell Tharani,Kocagoncu Ece,Lawson Jennifer,Malhotra Paresh,Ridha Basil H.,Rowe James B.,Thomas Alan J.,Zamboni Giovanna,Zetterberg Henrik,Cader M. Zameel,Wade-Martins Richard,Lovestone Simon,Nevado-Holgado Alejo,Kormilitzin Andrey,Buckley Noel J.
Abstract
AbstractHuman iPSCs provide powerful cellular models of Alzheimer’s disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer’s disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous Aβ oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protectiveAPOEgenotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens.Graphical Abstract
Publisher
Cold Spring Harbor Laboratory