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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Free Radical Biology and Medicine

ISSN

0891-5849

e-ISSN

1873-4596

Svazek periodika

208

Číslo periodika v rámci svazku

NOV 2023

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

394-401

Kód UT WoS článku

001074678600001

EID výsledku v databázi Scopus

—