Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease.

Autor: Holubiec MI; Instituto de Investigación en Biomedicina de Buenos Aires IBioBA (MPSP-CONICET), Partner Institute of the Max Planck Society, Godoy Cruz 2390, CABA, 1425, Buenos Aires, Argentina; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina., Alloatti M; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina., Bianchelli J; Instituto de Investigación en Biomedicina de Buenos Aires IBioBA (MPSP-CONICET), Partner Institute of the Max Planck Society, Godoy Cruz 2390, CABA, 1425, Buenos Aires, Argentina., Greloni F; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina., Arnaiz C; Instituto de Investigación en Biomedicina de Buenos Aires IBioBA (MPSP-CONICET), Partner Institute of the Max Planck Society, Godoy Cruz 2390, CABA, 1425, Buenos Aires, Argentina., Gonzalez Prinz M; Instituto de Investigación en Biomedicina de Buenos Aires IBioBA (MPSP-CONICET), Partner Institute of the Max Planck Society, Godoy Cruz 2390, CABA, 1425, Buenos Aires, Argentina., Fernandez Bessone I; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina., Pozo Devoto V; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina., Falzone TL; Instituto de Investigación en Biomedicina de Buenos Aires IBioBA (MPSP-CONICET), Partner Institute of the Max Planck Society, Godoy Cruz 2390, CABA, 1425, Buenos Aires, Argentina; Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CABA, 1121, Buenos Aires, Argentina. Electronic address: tfalzone@fmed.uba.ar.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2023 Nov 01; Vol. 208, pp. 394-401. Date of Electronic Publication: 2023 Aug 30.
DOI: 10.1016/j.freeradbiomed.2023.08.028
Abstrakt: Reactive Oxygen Species (ROS) and mitochondrial dysfunction are implicated in the pathogenesis of Alzheimer's disease (AD), a common neurodegenerative disorder characterized by abnormal metabolism of the amyloid precursor protein (APP) in brain tissue. However, the exact mechanism by which abnormal APP leads to oxidative distress remains unclear. Damage to mitochondrial membrane and inhibition of mitochondrial respiration are thought to contribute to the progression of the disease. However, the lack of suitable human models that replicate pathological features, together with impaired cellular pathways, constitutes a major challenge in AD studies. In this work, we induced pluripotency in patient-derived skin fibroblasts carrying the Swedish mutation in App (APP swe ), to generate human brain organoids that model AD, and studied redox regulation and mitochondrial homeostasis. We found time-dependent increases in AD-related pathological hallmarks in APP swe brain organoids, including elevated Aβ levels, increased extracellular amyloid deposits, and enhanced tau phosphorylation. Interestingly, using live-imaging spinning-disk confocal microscopy, we found an increase in mitochondrial fragmentation and a significant loss of mitochondrial membrane potential in APP swe brain organoids when subjected to oxidative conditions. Moreover, ratiometric dyes in a live imaging setting revealed a selective increase in mitochondrial superoxide anion and hydrogen peroxide levels in APP swe brain organoids that were coupled to impairments in cytosolic and mitochondrial redoxin protein expression. Our results suggest a selective increase in mitochondrial vulnerability to oxidative conditions in APP swe organoids, indicating that the abnormal metabolism of APP leads to specific changes in mitochondrial homeostasis that enhance the vulnerability to oxidation in AD.
Competing Interests: Declaration of competing interest The authors declare no competing financial interests.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE