Abstract
Patient-specific stem cell technology from skin and other biopsy sources has transformed in vitro models of neurodegenerative disease, permitting interrogation of the effects of complex human genetics on neurotoxicity. However, the neuropathologic changes that underlie cognitive and behavioral phenotypes can only be determined at autopsy. To better correlate the biology of derived neurons with age-related and neurodegenerative changes, we generated leptomeningeal cell lines from well-characterized research subjects that have undergone comprehensive postmortem neuropathologic examinations. In a series of proof of principle experiments, we reprogrammed autopsy leptomeningeal cell lines to human-induced pluripotent stem cells (hiPSCs) and differentiated these into neurons. We show that leptomeningeal-derived hiPSC lines can be generated from fresh and frozen leptomeninges, are pluripotent, and retain the karyotype of the starting cell population. Additionally, neurons differentiated from these hiPSCs are functional and produce measurable Alzheimer disease-relevant analytes (Aβ and Tau). Finally, we used direct conversion protocols to transdifferentiate leptomeningeal cells to neurons. These resources allow the generation of in vit...Continue Reading
References
Jul 1, 2007·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Ron BrookmeyerH Michael Arrighi
Apr 5, 2011·Nature Methods·Keisuke OkitaShinya Yamanaka
Nov 22, 2011·Acta Neuropathologica·Thomas J MontineUNKNOWN Alzheimer’s Association
Oct 3, 2012·PloS One·Lindsay A BlissThomas M Hyde
May 15, 2013·Journal of Alzheimer's Disease : JAD·Brenna CholertonThomas J Montine
Jan 9, 2014·Acta Neuropathologica Communications·Andrew A SproulScott A Noggle
Mar 8, 2014·Molecular Cytogenetics·Yuri B YurovIvan Y Iourov
Mar 17, 2015·Cell Stem Cell·Jessica E YoungLawrence S B Goldstein
Oct 13, 2015·Cell Stem Cell·Jerome MertensFred H Gage
Dec 15, 2015·Molecular and Cellular Neurosciences·Alison E MungenastLi-Huei Tsai
May 28, 2016·American Journal of Human Genetics·Jan P DumanskiLars A Forsberg
Oct 18, 2016·ELife·Christine J HuhAndrew S Yoo
Nov 28, 2016·Cell Stem Cell·Francesco BifariPeter Carmeliet
Mar 14, 2017·Stem Cell Reports·Philip W BrownjohnFrederick J Livesey
Citations
Feb 16, 2019·Stem Cells and Development·Mikiya BeppuShinichi Yoshimura
Nov 2, 2019·CPT: Pharmacometrics & Systems Pharmacology·Hugo GeertsMary Pelleymounter
Mar 15, 2020·Journal of Neuroscience Research·Gary X D'SouzaJessica E Young
Mar 18, 2020·Molecular Neurodegeneration·Jonathan FrewHaakon B Nygaard
Feb 8, 2019·Journal of Biomedical Science·Fernanda MajoloJaderson Costa Da Costa
Jun 4, 2020·Cell Reports·Allison KnuppJessica E Young
Apr 4, 2021·International Journal of Molecular Sciences·Harald FrankowskiJessica E Young