IPSCs-derived nerve-like cells from familial Alzheimer's disease PSEN 1 E280A reveal increased amyloid-beta levels and loss of the Y chromosome. (11th June 2019)

• Record Type: Journal Article
• Authors: Mendivil-Perez, Miguel; Velez-Pardo, Carlos; Kosik, Kenneth S.; Lopera, Francisco; Jimenez-Del-Rio, Marlene
• Is Part Of: Neuroscience letters. Volume 703(2019)
• Page Start: 111
• Page End: 118
• Publication Date: 2019-06-11
• Subjects: Familial Alzheimer disease -- Chromosome Y -- E280A -- iPSCs -- PSEN1; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2019.03.032
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: iPSCs were produced from a familial Alzheimer's disease male patient.iPSCs FAD carried a PSEN1 E280A mutation in PSEN1 gene. PSEN1 E280A iPSCs secrete higher concentration of Aβ1-42. iPSCs PSEN1 E280A can be successfully differentiated into NPC.iPSCs PSEN1 E280A derived NPC failed to differentiate into neurons. iPSCs PSEN1 E280A clone displayed LOY chromosome. Abstract: Alzheimer's disease (AD) is a progressive, degenerative disorder that mainly results in memory loss and a cognitive disorder. Although the cause of AD is still unknown, a minor percentage of AD cases are produced by genetic mutations in the presenilin-1 ( PSEN1 ) gene. Differentiated neuronal cells derived from induced pluripotent stem cells (iPSCs) of patients can recapitulate key pathological features of AD in vitro ; however, iPSCs studies focused on the p.E280 A mutation, which afflicts the largest family in the world with familial AD, have not been carried out yet. Although a link between the loss of the Y (LOY) chromosome in peripheral blood cells and risk for AD has been reported, LOY-associated phenotype has not been previously studied in PSEN1 E280 A carriers. Here, we report the reprogramming of fibroblast cells into iPSCs from a familial AD patient with the PSEN1 E280 A mutation, followed by neuronal differentiation into neural precursor cells (NPCs), and the differentiation of NPCs into differentiated neurons that lacked a Y chromosome. Although the PSEN1 E280 A iPSCs and NPCs were successfully obtained, after 8 days of differentiation, PSEN1 E280 A differentiated neurons massively died reflected by release and/ or activation of death markers, and failed to reach complete neural differentiation compared to PSEN 1 wild type cells.