Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying a L150P mutation in PSEN-1

Tubsuwan, Alisa; Pires, Carlota; Rasmussen, Mette; Schmid, Benjamin; Nielsen, Jørgen E.; Hjermind, Lena E.; Hall, Vanessa Jane; Nielsen, Troels Tolstrup; Waldemar, Gunhild; Hyttel, Poul; Clausen, Christian; Kitiyanant, Narisorn; Freude, Kristine; Holst, Bjørn

doi:10.1016/j.scr.2015.12.015

Cited by 24 publications

(16 citation statements)

References 3 publications

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“…Although APP (Jonsson et al, 2012), APOE (Morris et al, 2010) and PSEN (Hjermind, 2016) have been recognized as genetic risk factors of AD, we have not identified them in the diagnostic biomarkers because they are not differentially expressed genes in any of the six brain regions. It is of interest to study the relationship between biomarkers and AD genes.…”

Section: Discussionmentioning

confidence: 95%

Detecting Diagnostic Biomarkers of Alzheimer's Disease by Integrating Gene Expression Data in Six Brain Regions

Wang

Liu

2019

Front. Genet.

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Alzheimer's disease (AD) is a neurodegenerative and progressive disease, which often causes irreversible damages to the cerebrum. The pathogenesis of AD is far from being fully understood, while there are some popular hypotheses. So far, the diagnosis of AD relies only on clinical screening in the form of imaging techniques or cerebrospinal fluid analysis, which may lead to inaccurate evaluation and then cause the delay of suitable treatments. While molecular biomarkers provide promising alternatives of establishing correct relationships between genotypes and phenotypes of clinical symptoms. In this paper, we propose a machine-learning-based method of identifying potential diagnostic biomarkers of AD based on gene coexpression network by integrating gene expression profiles in six brain regions. After building an integrated gene coexpression network of multiple brain regions, we decompose the differential network into some subnetwork modules. The module candidates from these coexpressed gene communities are then identified by screening their discriminative powers in control from disease samples. The potential biomarkers are then validated by multiple cross-validations and functional enrichment analyses. If the biomarkers successfully pass clinical significance tests, they can be used as a reference for clinical diagnosis after wet-experimental validations.

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Section: Discussionmentioning

confidence: 95%

Detecting Diagnostic Biomarkers of Alzheimer's Disease by Integrating Gene Expression Data in Six Brain Regions

Wang

Liu

2019

Front. Genet.

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“…Recent advances in iPSC technology have highlighted the importance of metabolic dysfunction in the progression of AD. Our hope and expectation is that under-standing the molecular mechanisms underlying this metabolic dysfunction will reveal novel therapeutic targets for this devastating disease[168-177].…”

Section: Resultsmentioning

confidence: 99%

Modelling mitochondrial dysfunction in Alzheimer's disease using human induced pluripotent stem cells

Hawkins

Duchen

2019

WJSC

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Alzheimer’s disease (AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells (iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aβ and tau, oxidative stress and mitochondrial dysfunction, sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.

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“…The reported M146I-iPSCs line may be a useful resource for in vitro modeling of FAD.2016Li et al [64]Disease model; A79V mutationA79V-iPSCs were free of genomically integrated reprogramming genes, had the specific mutation but no additional genomic aberrancies, expressed the expected pluripotency markers and displayed in vitro differentiation potential to the three germ layers.2016Li et al [65]L150P mutationThe iPSCs were established by co-electroporation with episomal plasmids containing hOCT4, hSOX2, hL-MYC, hKLF4, hNANOG, hLIN28, and short hairpin RNA against TP53. The iPSCs contained the specific heterozygous mutation c.449C > T, had normal karyotype, expressed the expected pluripotency genes and displayed in vitro differentiation potential to the three germ layers.2016Tubsuwan et al [123]3 different mutations; GSMBiomarker signatures obtained with such models are misleading and that human neurons derived from hiPSCs provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.2014Liu et al [68]Non integrating vectorsNeurons from mutant hiPSC lines express PS1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of APP indicated by an increase in Aβ42/Aβ40 ratio.2014Mahairaki et al [70]NPCsPS1 mutant fibroblasts and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PS1 NPCs than in fibroblasts.2014Sproul et al [116]Allelic series mutations;FAD PS1 mutations do not act as simple loss of PS1 function but instead dominantly gain an activity toxic to some, but not all, PS1 functions.2013Woodruff et al [129]Proteolytic APP processingThe human NSC-derived neurons express the neuron-specific APP(695) splice variant, BACE1, and all members of the γ-secretase complex. They also exhibit a differentiation-dependent increase in Aβ secretion and respond to the pharmacotherapeutic modulation by anti-amyloidogenic compounds, such as γ-secretase inhibitors and nonsteroidal anti-inflammatory drugs.2012Koch et al [54]Aβ42 secretionFAD-iPSCs-derived differentiated neurons have increased toxic Aβ42 secretion, recapitulating the molecular pathogenesis of mutant presenilins.…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Important advances in Alzheimer’s disease from the use of induced pluripotent stem cells

2019

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Among the various types of dementia, Alzheimer’s disease (AD) is the most prevalent and is clinically defined as the appearance of progressive deficits in cognition and memory. Considering that AD is a central nervous system disease, getting tissue from the patient to study the disease before death is challenging. The discovery of the technique called induced pluripotent stem cells (iPSCs) allows to reprogram the patient’s somatic cells to a pluripotent state by the forced expression of a defined set of transcription factors. Many studies have shown promising results and made important conclusions beyond AD using iPSCs approach. Due to the accumulating knowledge related to this topic and the important advances obtained until now, we review, using PubMed, and present an update of all publications related to AD from the use of iPSCs. The first iPSCs generated for AD were carried out in 2011 by Yahata et al. (PLoS One 6:e25788, 2011) and Yaqi et al. (Hum Mol Genet 20:4530–9, 2011). Like other authors, both authors used iPSCs as a pre-clinical tool for screening therapeutic compounds. This approach is also essential to model AD, testing early toxicity and efficacy, and developing a platform for drug development. Considering that the iPSCs technique is relatively recent, we can consider that the AD field received valuable contributions from iPSCs models, contributing to our understanding and the treatment of this devastating disorder.

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Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying a L150P mutation in PSEN-1

Cited by 24 publications

References 3 publications

Detecting Diagnostic Biomarkers of Alzheimer's Disease by Integrating Gene Expression Data in Six Brain Regions

Detecting Diagnostic Biomarkers of Alzheimer's Disease by Integrating Gene Expression Data in Six Brain Regions

Modelling mitochondrial dysfunction in Alzheimer's disease using human induced pluripotent stem cells

Important advances in Alzheimer’s disease from the use of induced pluripotent stem cells

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