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World J Stem Cells. Apr 26, 2014; 6(2): 239-247
Published online Apr 26, 2014. doi: 10.4252/wjsc.v6.i2.239
Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology
Lisa Mohamet, Natalie J Miazga, Christopher M Ward
Lisa Mohamet, Natalie J Miazga, Christopher M Ward, Stem Cell Biology Group, Core Technology Facility, Faculty of Human and Medical Sciences, The University of Manchester, Manchester M13 9NT, United Kingdom
Author contributions: Mohamet L, Miazga NJ and Ward CM contributed to research, writing and editing of paper.
Supported by United Kingdom Biotechnology and Biosciences Research Council, Engineering and Physical Sciences Research Council and the Technology Strategy Board
Correspondence to: Dr. Christopher M Ward, Stem Cell Biology Group, Core Technology Facility, Faculty of Human and Medical Sciences, The University of Manchester, Manchester, 46 Grafton Street, Manchester M13 9NT, United Kingdom. christopher.ward@manchester.ac.uk
Telephone: +44-161-2755182 Fax: +44-161-2755182
Received: December 4, 2013
Revised: February 7, 2014
Accepted: February 18, 2014
Published online: April 26, 2014
Processing time: 144 Days and 20.2 Hours
Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro. We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years.

Keywords: Human induced pluripotent stem cells; Alzheimer’s disease; Neurodegenerative diseases; High-throughput screening assays; Cholinergic neurons; Drug discovery; Stratified medicine

Core tip: Alzheimer’s disease (AD) affects 36 million people worldwide and is set to double by 2030. Progress in understanding AD has been hindered by a lack of suitable in vitro and in vivo models reflected in > 90% drug attrition rates. Induced pluripotent stem cells are an alternative source of neural cells that can be derived from patients’ somatic cells and exhibit AD pathophysiological phenotypes. These cells are amenable to HTS formats required for drug discovery applications. Harnessing this combined potential would provide an unprecedented opportunity to significantly reduce timeframes and costs associated with developing novel therapeutics, ultimately improving patient outcomes.