Characterization and Molecular Profiling of PSEN1 Familial Alzheimer's Disease iPSC-Derived Neural Progenitors

Sproul, Andrew A.; Shvero, Jacob; Pré, Deborah; Kim, Soong Ho; Nestor, Michael W.; Navarro-Sobrino, Míriam; Santa-María, Ismael; Zimmer, Matthew; Aubry, S.; Steele, John W.; Kahler, David J.; Dranovsky, Alex; Arancio, Ottavio; Crary, John F.; Gandy, Sam; Noggle, Scott

doi:10.1371/journal.pone.0084547

Cited by 150 publications

(121 citation statements)

References 51 publications

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“…On the contrary, no accumulation of tau protein was observed in this type of FAD-derived neurons, revealing that at least for that genotype this protein may not be the main cause of ailment [12,15,20]. Indeed, some studies have showed that iNs and iPSCs-derived neurons from FAD patient fibroblasts had an increased Aβ42/Aβ40 ratio that resembles that observed in AD brains [10,21,22]. Similarly, human iNs from familial AD patients recapitulated the pathology of altered processing and aberrant endosomal localization of APP as well as increased production of Aβ peptides [23].…”

Section: Discussionmentioning

confidence: 73%

Out with the Old, in with the New… Strategies Based on Stem Cells to Design New Models of Alzheimer’s Disease

Revilla¹

2017

JSRT

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Since Yamanaka's group successfully discovered iPSCs technology a decade ago, new approaches for disease modeling have happened in the field. iPSCs have become the primary alternative to ESCs and is considered as a potential tool for modeling neurodegenerative diseases. The most prevalent form of dementia worldwide is AD, with aging being the major risk factor to develop it. Although it was described more than a hundred years ago, currently it doesn't exist a cure for this disorder, and ordinary treatments can only temporarily alleviate their symptoms. It has been reported that only 5% of AD cases are inherited, showing the remaining 95% a sporadic origin. Our understanding of AD pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the limitations to model the sporadic form of the disease. Given that, iPSCs can be derived from somatic cells of AD patients and subsequently be differentiated into neurons, the development of therapies based on the use of stem cells might be a promising novel tool for cellular replacement therapy, in addition to disease modeling and drug discovery for AD. Direct reprogramming, cocktails of small molecules, gene editing or 3D cell culture are among those new strategies that are improving the application of stem cells in regenerative medicine. Here, we show how present approaches in the field of iPSCs can contribute to create novel AD disease models.

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Section: Discussionmentioning

confidence: 73%

Out with the Old, in with the New… Strategies Based on Stem Cells to Design New Models of Alzheimer’s Disease

Revilla¹

2017

JSRT

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“…In one study, no tau accumulation or tangle formation was observed [51]. One other study has reported small changes in gene function in PSEN1 mutant iPSC-derived neurons, including increased NLRP2, ASB9 and NDP [53]. In addition, overexpression of PSEN1 in human ESCs led to increased Aβ42/Aβ40 and Aβ43/Aβ40 ratios as well as synaptic dysfunction in neurons expressing NeuN and BIII-tubulin [56].…”

Section: Psen1 Mutationsmentioning

confidence: 96%

“…These studies have revealed that most of the neurons generated from PSEN1 AD patients also have increased Aβ42 [51][52][53][54], although decreases in Aβ40 have also been described in two particular mutations [55]. However, little other pathology has been described.…”

Section: Psen1 Mutationsmentioning

confidence: 99%

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

Hall¹

2016

Pluripotent Stem Cells - From the Bench to the Clinic

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Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer's disease, frontotemporal dementia and Parkinson's disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only some of the phenotype can be observed in-vitro, but these phenotypes, when compared to the patient, correlate extremely well. Many studies have found novel molecular mechanisms involved in the disease and therefore elucidate new potential targets for reversing the phenotype. Future research that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about these diseases, but will lead to even more findings in the future as gene and cell culture technology continues to develop.

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“…[39][40][41] Pluripotent stem cells (PSCs) are primarily used as the cell source due to their capacity for self-organization through processes of self-assembly, self-patterning, and self-driven morphogenesis. [42][43][44] Independent of the approach used to develop 3D printing models, accurately recapitulating key aspects of the in vivo environment remains a major challenge. [45][46][47][48] A fundamental understanding of native tissues and organs is first needed before mimicking these in in vitro cultures.…”

Section: Engineering Technologiesmentioning

confidence: 99%

3D Miniaturization of Human Organs for Drug Discovery

Park

Wetzel

Dréau

et al. 2017

Adv Healthcare Materials

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“Engineered human organs” hold promises for predicting the effectiveness and accuracy of drug responses while reducing cost, time, and failure rates in clinical trials. Multiorgan human models utilize many aspects of currently available technologies including self‐organized spherical 3D human organoids, microfabricated 3D human organ chips, and 3D bioprinted human organ constructs to mimic key structural and functional properties of human organs. They enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues. Thus, engineered human organs can provide the microstructures and biological functions of target organs and advantageously substitute multiscaled drug‐testing platforms including the current in vitro molecular assays, cell platforms, and in vivo models. This review provides an overview of advanced innovative designs based on the three main technologies used for organ construction leading to single and multiorgan systems useable for drug development. Current technological challenges and future perspectives are also discussed.

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Characterization and Molecular Profiling of PSEN1 Familial Alzheimer's Disease iPSC-Derived Neural Progenitors

Cited by 150 publications

References 51 publications

Out with the Old, in with the New… Strategies Based on Stem Cells to Design New Models of Alzheimer’s Disease

Out with the Old, in with the New… Strategies Based on Stem Cells to Design New Models of Alzheimer’s Disease

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

3D Miniaturization of Human Organs for Drug Discovery

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