Stem cell therapy for Alzheimer’s disease and related disorders: current status and future perspectives

OPEN Experimental & Molecular Medicine (2015) 47, e151; doi:10.1038/emm.2014.124 & 2015 KSBMB. All rights reserved 2092-6413/15 www.nature.com/emm REVIEW Stem cell therapy for Alzheimer’s disease and related disorders: current status and future perspectives Leslie M Tong1,2, Helen Fong1,3 and Yadong Huang1,2,3,4 Underlying cognitive declines in Alzheimer’s disease (AD) are the result of neuron and neuronal process losses due to a wide range of factors. To date, all efforts to develop therapies that target specific AD-related pathways have failed in late-stage human trials. As a result, an emerging consensus in the field is that treatment of AD patients with currently available drug candidates might come too late, likely as a result of significant neuronal loss in the brain. In this regard, cell-replacement therapies, such as human embryonic stem cell- or induced pluripotent stem cell-derived neural cells, hold potential for treating AD patients. With the advent of stem cell technologies and the ability to transform these cells into different types of central nervous system neurons and glial cells, some success in stem cell therapy has been reported in animal models of AD. However, many more steps remain before stem cell therapies will be clinically feasible for AD and related disorders in humans. In this review, we will discuss current research advances in AD pathogenesis and stem cell technologies; additionally, the potential challenges and strategies for using cell-based therapies for AD and related disorders will be discussed. Experimental & Molecular Medicine (2015) 47, e151; doi:10.1038/emm.2014.124; published online 13 March 2015 INTRODUCTION Alzheimer’s disease (AD) is clinically characterized by progressive loss of memory and other cognitive functions. Typically, several years pass between the initial onset of symptoms and eventual death. AD is estimated to have cost the US $172 billion and the world $604 billion in 2010 alone.1 These costs are staggering in light of predictions that the number of AD cases worldwide, currently estimated at 36 million, will triple by 2050.1 Therefore, there is a pressing need to identify novel mechanisms and develop new therapeutic strategies for AD. The complexity and multifactorial nature of AD poses unique challenges for pathogenic studies and therapeutic developments.2 Efforts to target AD-related pathways have shown promise in animal studies only to fail during human trials.2,3 An emerging consensus in the field is that treatment of AD patients with currently available drug candidates comes too late, likely as a result of significant neuronal loss in the brain. In this regard, cell-replacement therapies, such as human embryonic stem cell (ESC)- or induced pluripotent stem cell (iPSC)derived neural cells, hold potential for treating AD patients who may be beyond the help of pharmacological therapies.4 We will briefly review the current state of research in AD pathogenesis and new stem cell technologies. Additionally, the 1 potential challenges and strategies for using cell-based therapies for AD and related disorders will be discussed. We will also highlight recent studies that have obtained or developed promising cell types that could be used to defeat this devastating disease in the future. ADVANCEMENT OF RESEARCH IN AD PATHOGENESIS Genetics of AD pathogenesis It is well known that the brains of AD patients accumulate two types of classically misfolded proteins. The first is amyloid-beta (Aβ), which is the pathological cleavage product of the amyloid precursor protein (APP).2 Aβ accumulates into plaques and smaller oligomers.2 Mutations in APP or in proteins involved in APP processing are well documented as being linked to inherited familial AD, an early-onset autosomal-dominant form of the disease that begins before the age of 65 years but only accounts for o2% of all AD cases.2 Many of the failed drugs in clinical trials directly or indirectly target this pathway with small molecules or antibody therapies to decrease Aβ production or promote Aβ clearance.2,3 The second of the misfolded proteins in AD is tau, a microtubule-associated protein that accumulates intracellularly as neurofibrillary tangles, a pathological feature that most closely correlates with Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA; 2Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA; 3Department of Neurology, University of California, San Francisco, CA, USA and 4Department of Pathology, University of California, San Francisco, CA, USA Correspondence: Dr Y Huang, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA. E-mail: Received 4 November 2014; accepted 19 November 2014 Stem cell therapy for Alzheimer’s disease LM Tong et al 2 cognitive decline in AD.2 However, mutations in tau usually cause frontotemporal dementia but not AD.2 The vast majority (498%) of AD cases, which do not involve mutations in genes of APP-processing pathways, are sporadic with onset beginning over the age of 65 years.2 For this population, the strongest predictor of developing AD, aside from age, is the genetic risk factor apolipoprotein (apo) E4.2 Each individual carries two copies of the apoE gene that exists in three allelic forms, ε2, ε3 and ε4, that encode three corresponding isoforms: apoE2, apoE3 and apoE4, respectively.5 Importantly, apoE4 carriers make up 60–75% of AD cases although those individuals only represent approximately 25% of the normal population. AD patients with apoE4 have a younger age of disease onset relative to non-carrier patients.6 All well-conducted genome-wide association studies on late-onset AD from different populations around the world have identified, with extremely high confidence, apoE4 as the top late-onset AD gene.7 Remarkably, the lifetime risk estimate of developing AD for individuals with two copies of the apoE4 allele (approximately 2% of the population) is approximately 60% by the age of 85 years and for those with one copy of the apoE4 allele (approximately 25% of the population), approximately 30%.8 In comparison, the lifetime risk of AD for those with two copies of the apoE3 allele is approximately 10% by the age of 85 years. Thus apoE4 should be considered a major gene with semi-dominant inheritance for late-onset AD.8 Interestingly, carriers of apoE2, the rarest isoform, have a decreased risk for developing AD compared with homozygous carriers of apoE3.6 Genome-wide association studies also identified other genes that modulate the risk of late-onset AD, including CLU, CR1, PICALM, BIN1, SORL1, GAB2, ABCA7, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and HLADRB1/5.7 However, the relative contribution of these genes to AD is modest compared with apoE4. Aβ and AD pathogenesis Diverse lines of evidence suggest that APP and Aβ contribute causally to the pathogenesis of early-onset familial AD, although to what ex (...truncated)