APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation

Mertens, Jérôme; Stüber, Kathrin; Wunderlich, Patrick; Ladewig, Julia; Kesavan, Jaideep; Vandenberghe, Rik; Vandenbulcke, Mathieu; Damme, Philip Van; Walter, Jochen; Brüstle, Oliver; Koch, Philipp

doi:10.1016/j.stemcr.2013.10.011

Cited by 60 publications

(49 citation statements)

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“…To assess ARSA enzyme activity in lt-NES cells, APCs and their differentiated progeny, we performed enzymatic ARSA activity assays using the artificial substrate p-nitrocatechol sulfate. As healthy controls we included lt-NES cells and APCs from an unaffected donor(22,23). This assay revealed a strongly reduced ARSA activity in the MLD patient-derived cells compared to healthy control cells(Figure 3C).…”

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confidence: 99%

Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy

et al. 2015

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Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 µm from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue.

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Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy

et al. 2015

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“…Although some of the mutations studied so far might increase the production of Aβ42, most mutations decreased the secretion of Aβ40 peptides (76,77). PS FAD-associated mutations also decrease the secretion of Aβ40 more strongly than Aβ42 in induced pluripotent or embryonic stem cell-derived human neurons, further supporting a partial loss of γ-secretase function of PS FAD mutants (78,79).…”

Section: N V I T E D R E V I E W a R T I C L Ementioning

confidence: 84%

Twenty Years of Presenilins—Important Proteins in Health and Disease

Walter

2015

Mol Med

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Alzheimer's disease (AD) is characterized by progressive decline in cognitive functions associated with depositions of aggregated proteins in the form of extracellular plaques and neurofibrillary tangles in the brain. Extracellular plaques contain characteristic fibrils of amyloid β peptides (Aβ); tangles consist of paired helical filaments of the microtubuli-associated protein tau. Although AD manifests predominantly at ages above 65 years, rare cases show a much earlier onset of disease symptoms with very similar neuropathological characteristics. In 1995, two homologous genes were identified, in which mutations are associated with dominantly inherited familial forms of early onset AD. The genes therefore were dubbed presenilins (PS) and encode polytopic transmembrane proteins. At this time the role of these proteins in the pathogenesis of AD and their biological function in general were completely unknown. However, individuals carrying PS mutations showed alterations in the composition of different length variants of Aβ peptides in blood and cerebrospinal fluid, which indicated the potential involvement of presenilins in the metabolism of Aβ. After 20 years of intense research, the roles of presenilins in Aβ generation as well as important functions in biological processes have been identified. Presenilins represent the catalytic components of protease complexes that directly cleave the amyloid precursor protein (APP) but also many other proteins with important physiological functions. Here, the progress in presenilin research from basic characterization of their cellular functions to the targeting in clinical trials for AD therapy, and potential future directions, will be discussed.

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“…Even a single amino acid change in proteins between mouse and human can change pharmacological responsiveness (10, 11). Transgenic animal models often express multiple copies of disease-associated mutant human transgenes, but patients generally express only a single allele (12), and even with elevated levels of the mutant human protein, many animal models recapitulate only a subset of the human pathologies.…”

Section: Do Preclinical Tests In Animal Models Correlate With Clinicamentioning

confidence: 99%

Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases

Haston

Finkbeiner

2016

Annu. Rev. Pharmacol. Toxicol.

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Neurodegenerative diseases are a leading cause of death. No disease-modifying therapies are available, and preclinical animal model data have routinely failed to translate into success for therapeutics. Induced pluripotent stem cell (iPSC) biology holds great promise for human in vitro disease modeling because these cells can give rise to any cell in the human brain and display phenotypes specific to neurodegenerative diseases previously identified in postmortem and clinical samples. Here, we explore the potential and caveats of iPSC technology as a platform for drug development and screening, and the future potential to use large cohorts of disease-bearing iPSCs to perform clinical trials in a dish.

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APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation

Cited by 60 publications

References 33 publications

Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy

Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy

Twenty Years of Presenilins—Important Proteins in Health and Disease

Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases

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