Abstract
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.
Highlights
U Abbreviations: AD, Alzheimer's disease; AGD, argyrophilic grain disease; APP, amyloid precursor protein; Aβ, amyloid β; CBD, corticobasal degeneration; CSF, cerebrospinal fluid; Down's syndrome (DS), down's syndrome; FTD, frontotemporal dementia; GGT, globular glial tauopathy; human embryonic stem cells (hESC), human embryonic stem cell; IP, immunoprecipitation; Induced pluripotent stem cell (iPSC), induced pluripotent stem cell; LC-Mass spectrometry (MS)/MS, liquid chromatography –tandem mass spectrometry; MALDI, TOF, matrix-assisted laser desorption/ionization with time-of-flight; MAPT, microtubule-associated protein tau gene; MS, mass spectrometry; PART, primary age-related tauopathy; PiD, Pick's disease; PRM, parallel reaction monitoring; PSEN1, presenillin-1; PSEN2, presenillin-2; PSP, progressive supranuclear palsy; post-translational modifications (PTMs), post-translational modification; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; surface enhancement laser desorption/ionization (SELDI)-TOF, surface-enhanced laser desorption/ionization—time-of-flight; Stable isotope labelling kinetics (SILK), stable isotope labelling kinetics
We focus on insights gained from the use of mass spectrometry in conjunction with these models, and how this has enabled the precise measurement of peptide isoforms, cleavage fragments, multimeric species and post-translational modifications
Mass spectrometry has been critical in detecting and distinguishing between various Aβ species in human brain tissue, CSF and plasma, and these approaches have recently been applied to iPSC models of AD
Summary
U Abbreviations: AD, Alzheimer's disease; AGD, argyrophilic grain disease; APP, amyloid precursor protein; Aβ, amyloid β; CBD, corticobasal degeneration; CSF, cerebrospinal fluid; DS, down's syndrome; FTD, frontotemporal dementia; GGT, globular glial tauopathy; hESC, human embryonic stem cell; IP, immunoprecipitation; iPSC, induced pluripotent stem cell; LC-MS/MS, liquid chromatography –tandem mass spectrometry; MALDI, TOF, matrix-assisted laser desorption/ionization with time-of-flight; MAPT, microtubule-associated protein tau gene; MS, mass spectrometry; PART, primary age-related tauopathy; PiD, Pick's disease; PRM, parallel reaction monitoring; PSEN1, presenillin-1; PSEN2, presenillin-2; PSP, progressive supranuclear palsy; PTM, post-translational modification; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; SELDI-TOF, surface-enhanced laser desorption/ionization—time-of-flight; SILK, stable isotope labelling kinetics. Multiple in vitro and in vivo models of AD and FTD exist, it is only recently that induced pluripotent stem cell (iPSC) technology has enabled the generation of unlimited numbers of human neurons in the lab. We focus on insights gained from the use of mass spectrometry in conjunction with these models, and how this has enabled the precise measurement of peptide isoforms, cleavage fragments, multimeric species and post-translational modifications.
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