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

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.

BMP4-SMAD1/5/9-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimer’s patients’ iPSCs in senescence-related conditions

“…However, several recent studies have successfully recapitulated some core phenotypes of age-related diseases ( Kondo et al., 2017 ; Nicaise et al., 2020 ), which may be explained by polygenic influences or epigenetic markers not eliminated by reprogramming. With AD, researchers created a model cell system that mimicked Aβ or tau abnormalities ( Arber et al., 2021 ; Schulz, 2021 ). The iPSC-based drug screening mainly proposed novel candidate drugs for relieving Aβ deposition or neuronal cell death ( Kondo et al., 2017 ; Pasteuning-Vuhman et al., 2021 ).…”

Baseline Clinical and Biomarker Characteristics of Biobank Innovations for Chronic Cerebrovascular Disease With Alzheimer’s Disease Study: BICWALZS

“…Patient-derived dermal fibroblasts are invaluable biospecimens that have great potential for ex vivo research and disease modeling using iPSCs or brain organoid generation. 15,40,41 One of our research teams is performing ex vivo research using patient-derived dermal fibroblasts to assess the cellular circadian rhythm of BICWALZS participants. In this biochemical experiment, we transfected a lentiviral vector (pABpuro-BluF) into patient-derived dermal fibroblasts and successfully measured Bmal1 transcriptional activity using a real-time luminometer.…”

Editorial: Exciting developments in neurochemistry research and publishing

“…We are excited to see the quality and diversity of the work submitted and accepted for publication by the Journal of Neurochemistry . From molecular mechanisms in cultured cells (Agbaegbu Iweka et al, 2021; Bendahmane et al, 2020), neurochemical mechanisms in intact organisms (Abreu et al, 2021; Becker et al, 2021), new imaging and quantitative methodologies providing insight into neurochemical changes (Abdalla et al, 2020; Arber et al, 2021; Blank & Hopf, 2021; Dienel, 2021) and critical biomarkers in disease (Altmayer et al, 2021; Chakraborty & Basu, 2021; Chatterjee et al, 2021; Eden et al, 2021; Geula et al, 2021; Ginsberg et al, 2021; Glezer et al, 2021), the scope of the Journal of Neurochemistry has broadened to respond to the demands of our scientific community. Neurochemical mechanisms of disease are a popular topic covering neuropsychiatric and developmental disorders (Haase et al, 2021; Kozlowska et al, 2021; Liu & McNally, 2021; Nie et al, 2021; Nomura et al, 2021) and neurodegenerative diseases (Brosseron et al, 2021; Butler et al, 2021; Chatterjee et al, 2021; Korecka & Shaw, 2021; Sathe et al, 2021; Trinh et al, 2021; Yuede et al, 2021).…”