Mass spectrometry analysis of tau and amyloid‐beta in iPSC‐derived models of Alzheimer’s disease and dementia

Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease‐associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC‐derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post‐translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC‐derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents. This Review is part of the special issue ‘Mass Spectrometry in Alzheimer Disease’ and will highlight the progress to date in studies using induced pluripotent stem cells (iPSCs) and mass spectrometry to model Alzheimer's disease and dementia. iPSCs represent a limitless source of dementia‐associated cell types of interest. These cells contain the precise genome of the donor or can be manipulated with novel genome editing techniques, such as CRISPR/Cas9. iPSCs can then be differentiated into any somatic cell type using developmental principles and growth factor signalling that mimics developmental patterning cues. Untargeted and targeted proteomic analysis using mass spectrometry can provide unparalleled insight to the fragments, modifications, aggregations and isoforms observed for key peptides of interest. Additionally, SILK studies (stable isotope labelling kinetics), which measure the incorporation of heavy isotope labelled tracers in proteins over time and is dependent on mass spectrometry, allow for peptide turnover investigations. Together, these techniques