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Tytuł pozycji:

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer's disease reveal intraneuronal sAPPβ fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications.

Tytuł :
Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer's disease reveal intraneuronal sAPPβ fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications.
Autorzy :
Soto-Mercado V; Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU Medellin, Medellin, Colombia.
Mendivil-Perez M; Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU Medellin, Medellin, Colombia.
Velez-Pardo C; Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU Medellin, Medellin, Colombia.
Lopera F; Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU Medellin, Medellin, Colombia.
Jimenez-Del-Rio M; Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU Medellin, Medellin, Colombia.
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Źródło :
PloS one [PLoS One] 2020 May 21; Vol. 15 (5), pp. e0221669. Date of Electronic Publication: 2020 May 21 (Print Publication: 2020).
Typ publikacji :
Journal Article; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Original Publication: San Francisco, CA : Public Library of Science
MeSH Terms :
Alzheimer Disease*/metabolism
Alzheimer Disease*/pathology
Cholinergic Neurons*/metabolism
Cholinergic Neurons*/pathology
Mesenchymal Stem Cells*/metabolism
Mesenchymal Stem Cells*/pathology
Presenilin-1*/genetics
Presenilin-1*/metabolism
Umbilical Cord*/metabolism
Umbilical Cord*/pathology
Amyloid Precursor Protein Secretases/metabolism ; Apoptosis ; Aspartic Acid Endopeptidases/metabolism ; Calcium/metabolism ; Humans ; Mutation ; Oxidative Stress ; tau Proteins/metabolism
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Substance Nomenclature :
0 (PSEN1 protein, human)
0 (Presenilin-1)
0 (tau Proteins)
EC 3.4.- (Amyloid Precursor Protein Secretases)
EC 3.4.23.- (Aspartic Acid Endopeptidases)
EC 3.4.23.46 (BACE1 protein, human)
SY7Q814VUP (Calcium)
Entry Date(s) :
Date Created: 20200522 Date Completed: 20200909 Latest Revision: 20200909
Update Code :
20201023
PubMed Central ID :
PMC7241743
DOI :
10.1371/journal.pone.0221669
PMID :
32437347
Czasopismo naukowe
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intracellular soluble amyloid precursor protein (sAPPf) fragments and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation provide important clues for the identification of targetable pathological molecules.
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