Induced pluripotent stem cells as a discovery tool for Alzheimer׳s disease

Abstract

The ability to accurately and systematically evaluate the cellular mechanisms underlying human neurodegenerative disorders such as Alzheimer's disease (AD) should lead to advancements in therapeutics. Recent developments in human induced pluripotent stem cells (iPSCs) have afforded the opportunity to use human neurons and glia to study cellular changes involved in neurological diseases. iPSCs have the potential to be differentiated into AD-relevant cell types, including forebrain neurons, astrocytes, and microglia. This permits the evaluation of individual cell types in isolation or in concert, thus modeling the interdependence of cell types within the brain. When discussing the potential of modeling AD with iPSCs, it is important to remember that the umbrella diagnosis of “Alzheimer's disease” represents a disease that is heterogeneous in terms of age of onset, underlying causes, and at times precise pathology. The ability of iPSCs to be derived from an array of AD patients allows for a closer examination of the mechanism of disease progression in particular subsets of subjects, who may have different mutations and allelic variants affecting their risk for disease. Disease mechanisms can be probed both by the genetic manipulation of iPSCs and by modifications to the cellular environment by chemical treatment. These studies may lead not only to the refinement of known pathways implicated in AD, but also to the identification of novel pathways heretofore unaffiliated with disease pathology. In this review, we describe the potential of iPSC models to transform our understanding of AD and to lead to valuable advancements in therapeutics.

The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism

“…The issue of causality should be pursued, although both in vitro systems such as human induced pluripotent stem cells differentiated to neurons [49] and in vivo murine or Drosophila models have limitations. In one example, an epigenomic profile of the CK-p25 mouse model, seems to have primarily indicated the presence of a large number of infiltrating myeloid cells, which may not be representative of other AD models [22] but may capture aspects of the human disease.…”

Stem Cells, Genome Editing, and the Path to Translational Medicine

“…Following in vitro differentiation, patient-derived hiPSCs provide disease-relevant somatic cells, which carry all the genetic elements implicated in the disease reflecting the genetic spectrum of the patient population. While discussing all of these studies is beyond the scope of this work, excellent recent reviews summarize hiPSC diseases models for neurodevelopmental (Ardhanareeswaran et al, 2017), neuropsychiatric (Hoffman et al, 2018) and neurodegenerative diseases including Alzheimer’s disease (Sullivan and Young-Pearse, 2017) and Parkinson’s disease (Shi et al, 2016; Zhang et al, 2017)), motor neuron and Huntington’s disease. The spectrum of phenotypes, which can be assessed in hiPSC-based in vitro models include a wide range of molecular, metabolic, cellular and electrophysiological analysis.…”

The use of human neurons for novel drug discovery in dementia research

“…Since these are all affected in tauopathies, it is important to use models in which these aspects of tau biology replicate the biology of adult human brain. Studies in non-pathological resected human brain tissue and patient iPSC derived neural models may be the best experimental paradigms for achieving this 43,100,101 . .…”