Modeling familial Alzheimer's disease with induced pluripotent stem cells

Yagi, Takuya; Ito, Daisuke; Okada, Yohei; Akamatsu, Wado; Nihei, Yoshihiro; Yoshizaki, Takahito; Yamanaka, Shinya; Okano, Hideyuki; Suzuki, Noriyuki

doi:10.1093/hmg/ddr394

Cited by 530 publications

(458 citation statements)

References 46 publications

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“…Furthermore, genetic and epigenetic variability among patients may influence pharmacological responsiveness [45]. Disease modeling using iPS cells for AD has been actively pursued recently and has shown that pharmacological assays can be readily performed using these models [46][47][48][49][50][51][52]. Modeling and screening using glial-neuron coculture and 3-dimensional cultures, both of which better resemble in vivo physiological states, should also be pursued [53,54].…”

Section: Phenotypic Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Phenotypic Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…for diseases with a known molecular mechanism, such as in spinal muscular atrophy, HutchinsonGilford Progeria syndrome, familial Parkinson's disease or Down syndrome (Ebben et al 2011;Malpass 2011;Jung et al 2012;Shi et al 2012). and PSEN2 (N141I), and characterized their subsequent differentiation into neurons (Yagi et al 2011). They found that FAD-iPSC-derived neurons showed increased Aβ42 secretion.…”

Section: Ad Disease Modelling With Ipscs -Identification Of Differencmentioning

confidence: 99%

“…They found that FAD-iPSC-derived neurons showed increased Aβ42 secretion. Furthermore, secretion of Aβ42 from these neurons sharply responds to γ-secretase inhibitors and modulators, indicating the potential for identification and validation of amyloid-lowering drugs (Yagi, Ito et al 2011;Yahata et al 2011). …”

Section: Ad Disease Modelling With Ipscs -Identification Of Differencmentioning

confidence: 99%

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

et al. 2012

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The use of induced pluripotent stem cells (iPSCs), whereby a patient's somatic cells can be reprogrammed to a pluripotent state by the forced expression of a defined set of transcription factors, has the potential to enable in vitro disease modelling and be used for drug discovery programs. Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to a decline in memory and cognition. Fibroblasts were taken from AD patients (or non‐AD controls) and cultured under specific conditions to generate iPSCs which were then provided with growth factors to allow differentiation into neurons. While AD‐iPSCs were morphologically indistinguishable from control‐iPSCs, differentiated cells showed differing responses to both cellular stresses and neuroprotective drugs. Since these cells are derived from individual patients, the use of iPSCs has provided novel insights into disease pathogenesis, providing information on an individual's variations in the disease process and their cellular response to drugs.

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“…Disease modeling based on iPSC technology has also been applied to many other neurological or psychiatry disorders, including Alzheimer's disease [32] , Huntington's disease [33,34] , Angelman and Prader-Willi syndromes [35,36] , schizophrenia [37] , and others (Table 1).…”

Section: Neurological Diseasesmentioning

confidence: 99%

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

Zhang

Xie

2013

Acta Pharmacol Sin

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The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.

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Modeling familial Alzheimer's disease with induced pluripotent stem cells

Cited by 530 publications

References 46 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

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