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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F23%3A00079680" target="_blank" >RIV/00159816:_____/23:00079680 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/abs/pii/S0891584923006081?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S0891584923006081?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.freeradbiomed.2023.08.028" target="_blank" >10.1016/j.freeradbiomed.2023.08.028</a>

Result language

angličtina

Original language name

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

Original language description

Reactive Oxygen Species (ROS) and mitochondrial dysfunction are implicated in the pathogenesis of Alzheimer&apos;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 respi-ration 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 (APPswe), 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 APPswe brain organoids, including elevated A beta 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 APPswe 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 APPswe 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 APPswe organoids, indicating that the abnormal metabolism of APP leads to specific changes in mitochondrial homeostasis that enhance the vulnerability to oxidation in AD.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Free Radical Biology and Medicine

ISSN

0891-5849

e-ISSN

1873-4596

Volume of the periodical

208

Issue of the periodical within the volume

NOV 2023

Country of publishing house

US - UNITED STATES

Number of pages

8

Pages from-to

394-401

UT code for WoS article

001074678600001

EID of the result in the Scopus database

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