Glycosylated clusterin species facilitate amyloid beta toxicity in human neurons.

Clusterin (CLU) is one of the most significant genetic risk factors for late onset Alzheimer’s disease. Numerous studies have now demonstrated that CLU-AD mutations and amyloid-β (Aβ) treatment alter the trafficking and localisation of glycosylated CLU. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control, unedited and exon 2 -/- iPSCs and were incubated with aggregated Aβ peptides. Changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ. RNA-Seq analysis was performed to identify key transcriptomic differences between exon 2 -/- and CTR neurons.