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Cellular Dynamics Poster Presentation at the EMBO | EMBL Symposium: Mechanisms of Neurodegeneration

Characterization of an Isogenic Disease Model of Alzheimer’s Disease from Human iPS Cell-derived Neurons

Authors: DeLaura S, Lange S, Carlson C, Aoyama N, Mangan K, McLachlan M, Burke T, and Jones E

Cellular Dynamics International – Madison, WI  53711 USA

Objectives: Mutations in the gene encoding beta amyloid precursor protein (APP) have been linked with the progression of Alzheimer’s Disease (AD). Leveraging our ability to produce previously inaccessible human neurons from iPS cells, we made biologically relevant AD disease models incorporating two APP mutations of interest as part of our Disease and Diversity Products that represent an array of both healthy and disease-specific backgrounds.

Methods: Using a TALEN-mediated SNP alteration, we introduced APP A673V or APP A673T gene mutations into a “control” iPS cell line (01279.107) from an apparently normal healthy Caucasian male donor (no family history of neurological disorders). Cortical neurons were differentiated from these three unique isogenic iPS cell lines. Gene expression was analyzed by target- and disease-focused PCR arrays. Levels of AD-related biomarkers (i.e., sAPPα, Aβ 1-40, and Aβ 1-42) were quantified using various HTS-compatible assays (i.e., HTRF and AlphaLISA). The network-level activity of neurons from each background was evaluated on multi-electrode array (MEA).

Results: Here, we present data characterizing the gene express and functionality of these neurons. Results from the HTS-compatible assays and MEA showed differences in functionality between the allele variants. Additionally, we present their individual responses to pharmacological modulation.

Conclusions: These data illustrate how human neurons derived from isogenic iPS cell lines provide a biologically relevant disease model that can be used to study AD in a dish.