Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

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.© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Human induced pluripotent stem cells; Alzheimer's disease; Neurodegenerative diseases; Highthroughput 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.Mohamet L, Miazga NJ, Ward CM. Familial Alzheimer's disease modelling using induced pluripotent stem cell technology. World J Stem Cells 2014; 6(2): 239-247 Available from:

3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

“…Human neurons derived from AD patients by iPSC technology appear to be an ideal platform for modeling AD in human neuronal environment [25, 26, 29, 30, 37–51]. To date, several research groups have reported the usage of iPSCs in AD modeling, which provide a proof-of-principle for modeling patient-specific AD pathology in human brain-like environment [25–30, 37–42, 48, 49, 52, 53].…”

“…To date, several research groups have reported the usage of iPSCs in AD modeling, which provide a proof-of-principle for modeling patient-specific AD pathology in human brain-like environment [25–30, 37–42, 48, 49, 52, 53]. These patient-derived AD neurons were mainly generated from FAD patients but also a few from sAD patients.…”

Concise Review: Modeling Central Nervous System Diseases Using Induced Pluripotent Stem Cells

“…iPSCs are reprogrammed stem cells that are akin to embryonic stem cells (ESCs), with the advantage of being able to be generated from any individual at any point. This offers the advantage of modeling diseases across a lifetime in a patientspecific manner [10,11]. Just as with their ESC counterparts, iPSCs can be maintained indefinitely, thus providing a limitless supply of well-characterized cells of a defined allelic phenotype.…”

iPSC-derived neurons as a tool for probing molecular pharmacology of antipsychotic action

“…Since the seminal generation of induced pluripotent stem cells (iPSCs) from human somatic cells (Takahashi et al, 2007), numerous studies have examined iPSC-neurons from patients, including those with schizophrenia (Brennand et al, 2012), autism (Shcheglovitov et al, 2013;Liu and Scott, 2014), ALS (Kondo et al, 2014), Alzheimer's (Mohamet et al, 2014), and Parkinson's disease (Ryan et al, 2013). These cells express components of a fully functional neuron, including cytoskeletal and synaptic proteins (Shi et al, 2012;Espuny-Camacho et al, 2013), the ability to generate action potentials (Boulting et al, 2011), and calcium transients (Boulting et al, 2011;Dage et al, 2014).…”