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Alzheimer’s Association International Conference

July 22 - July 26

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Join CDI at the AAIC 2018, where international investigators, clinicians and care providers gather to share the latest study results, theories and discoveries that will help bring the world closer to breakthroughs in dementia science. Come visit us at booth 830.

Poster Presentation

Poster Number : P3-163  Tuesday, July 24 | 9:30 am – 4:15 pm

Title:  Identification of Measurable Phenotypes Relevant to Alzheimer’s Disease Using Human iPSC-derived Neurons

Authors: Kile Mangan1, Lisa Harms1, Christian Kannemeier1, Kwi-Hye Kim1, Benjamin M Bader2, Konstantin Jügelt2, Olaf Schröder2, Beatriz Freitas1 and Eugenia Jones1

  1. Fujifilm Cellular Dynamics, Inc., Madison, WI, USA
  2. NeuroProof GmbH, Restock, Germany

Abstract: The development of therapies for Alzheimer’s disease (AD) has been hindered by limited availability of relevant cell models for basic research and drug discovery. Using induced pluripotent stem cell (iPSC) technology, we have created an unlimited source of human neurons available for studying the mechanisms of AD progression and to streamline the identification of novel drug treatments for this disease. A hallmark of AD pathology is the development of plaques in the brain that contain toxic beta amyloid peptides (Aß). Methods: We have taken two strategies to generate an iPSC-based “disease-in-a-dish” approach for modeling AD in vitro. The first is based on genome engineering of an apparently healthy normal iPSC line to introduce mutations in the gene coding for amyloid precursor protein (APP) and then create human neurons from genetically distinct samples. We rigorously tested the cells by high content imaging, PCR arrays, biomarker production, and multi-electrode array (MEA). Secondly, we have examined the effects of exogenous exposure to Aß peptides. Results: Our data were in general agreement with results observed in other model systems for A673V and A673T (known to influence and offer protection from AD progression, respectively). Uniquely presented, however, functional assessment on MEA with multi-parametric analysis revealed the APP A673V mutant had a significantly different phenotype than A673T or the isogenic WT control. Addition of oligomeric Aß(1-42) to GABAergic and glutamatergic neurons results in cytotoxicity as read out by ATP and LDH assays. Next, synchronous cultures of excitatory glutamatergic neurons – which can be analyzed on MEA to quantify bursting patterns, rates, intensities, and durations – display a dose-dependent decrease in network bursting prior to decay in firing rates and subsequent cell death. Detailed evaluation of the burst structure and action potential morphology will be presented. Importantly, these alterations were not observed in control experiments with Aß(1-40). Conclusions: Our studies demonstrate the utility of iPSC technology to create human cell models for AD that recapitulate some of this disease’s complex functional neuronal phenotypes. Ultimately, the promise is that such models might be used to screen for compounds that rescue these phenotypes.

Topic Selection:
[Posters Tuesday] Basic and Translational Science: Molecular and Cell Biology

Details

Start:
July 22
End:
July 26
Website:
https://www.alz.org/aaic/

Organizer

Alzheimer’s Association
Website:
https://www.alz.org/

Venue

McCormick Place
2301 S Martin Luther King Drive
Chicago, 60616 United States