eprintid: 10204211
rev_number: 6
eprint_status: archive
userid: 699
dir: disk0/10/20/42/11
datestamp: 2025-02-03 12:07:48
lastmod: 2025-02-03 12:07:48
status_changed: 2025-02-03 12:07:48
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Thirumalai, Srishruthi
creators_name: Livesey, Frederick J
creators_name: Patani, Rickie
creators_name: Hung, Christy
title: APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes
ispublished: pub
divisions: UCL
divisions: B02
divisions: D13
divisions: G22
keywords: Alzheimer's disease, antisense oligonucleotides, APP, astrocytes, Down syndrome, mitochondrial function
note: © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
abstract: INTRODUCTION: Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD). METHODS: Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy. RESULTS: APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production. DISCUSSION: APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings. HIGHLIGHTS: APP ASOs reduce APP levels in human iPSC-derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.
date: 2025-01
date_type: published
publisher: Wiley
official_url: https://doi.org/10.1002/alz.14560
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2357111
doi: 10.1002/alz.14560
medium: Print
lyricists_name: Hung, Oi Ying
lyricists_id: OYHHU52
actors_name: Hung, Oi Ying
actors_id: OYHHU52
actors_role: owner
funding_acknowledgements: [Alzheimer's Research UK]
full_text_status: public
publication: Alzheimer's & Dementia
volume: 21
number: 1
article_number: e14560
event_location: United States
citation:        Thirumalai, Srishruthi;    Livesey, Frederick J;    Patani, Rickie;    Hung, Christy;      (2025)    APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.                   Alzheimer's & Dementia , 21  (1)    , Article e14560.  10.1002/alz.14560 <https://doi.org/10.1002/alz.14560>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10204211/1/Alzheimer%20s%20%20%20Dementia%20-%202025%20-%20Thirumalai%20-%20APP%20antisense%20oligonucleotides%20are%20effective%20in%20rescuing%20mitochondrial.pdf