UK DRI researchers, together with leading colleagues in Alzheimer’s disease across UCL and beyond, have utilised patient-derived stem cells to uncover the effects of mutation on the processing of a key protein implicated in disease progression.
Published in Molecular Psychiatry, group members from Dr Selina Wray, Alzheimer’s Research UK-funded scientist, and UK DRI Professor Henrik Zetterberg at UCL, utilised the cells from patients with a familial form of the Alzheimer’s disease (fAD) and showed that common fAD mutations have distinct effects on the processing of amyloid beta, providing further understanding on disease mechanism.
Induced pluripotent stem cells (iPSC) are adult cells reprogrammed to an embryonic stem cell-like state. Since their discovery, researchers have been utilising the technique for modelling disease and drug development. In addition to insight gained on fAD mutation effects, the team established that measurements from iPSC-derived neurons closely replicated amyloid beta changes in matched samples from cerebrospinal fluid (CSF) and the brain itself, supporting their use as a valuable model system in Alzheimer’s disease research.
Joint lead author Henrik Zetterberg said:
“This research gives greater insight on how the different familial Alzheimer's disease (AD) mutations cause aberrant APP-processing and how the employed cell models could be used to examine this and screen for drugs that could neutralise the effects of the mutations (in a mutation/patient-specific manner). We also present the first correlations between CSF profiles from patients and their own neuronal amyloid beta secretome in the culture dish. What’s key in our findings is that amyloid beta ratios in the cell medium and in the patient CSF (same individual) are remarkably similar.
In the future, for people in a family with AD, we may be able to take a skin biopsy to create iPSC-derived neurons that can be analysed to select and adapt the right treatments and at the right dose.”
Joint lead author Selina Wray said:
“This work reveals deeper insights into the complex interaction between faulty genes and the proteins implicated in familial Alzheimer’s disease. Understanding the disease pathways that cause dementia in more detail is critical to help design and deliver new treatments that could help slow or stop disease progression.”
