APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes

Srishruthi Thirumalai; Frederick J. Livesey; Rickie Patani; Christy Hung

doi:10.1002/alz.14560

APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes

Srishruthi Thirumalai, Frederick J. Livesey, Rickie Patani^*, Christy Hung^*

^*Corresponding author for this work

Department of Neuroscience

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

7 Downloads (CityUHK Scholars)

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.

Original language	English
Article number	e14560
Number of pages	7
Journal	Alzheimer's and Dementia
Volume	21
Issue number	1
Online published	29 Jan 2025
DOIs	https://doi.org/10.1002/alz.14560
Publication status	Published - Jan 2025

Research Keywords

Humans
Induced Pluripotent Stem Cells/drug effects
Down Syndrome/metabolism
Astrocytes/drug effects
Mitochondria/drug effects
Amyloid beta-Protein Precursor/genetics
Oligonucleotides, Antisense/pharmacology
Phenotype
Cell Differentiation/drug effects
Alzheimer Disease/metabolism
Cells, Cultured
Superoxides/metabolism
Alzheimer’s disease
antisense oligonucleotides
APP
Down syndrome
mitochondrial function
astrocyte

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@article{7ef49a01ad96489f8f5f0df34a6ceb90,

title = "APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes",

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.{\textcopyright} 2025 The Author(s). ",

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author = "Srishruthi Thirumalai and Livesey, {Frederick J.} and Rickie Patani and Christy Hung",

note = "{\textcopyright} 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2025",

month = jan,

doi = "10.1002/alz.14560",

language = "English",

volume = "21",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley & Sons",

number = "1",

}

APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes. / Thirumalai, Srishruthi; Livesey, Frederick J.; Patani, Rickie et al.
In: Alzheimer's and Dementia, Vol. 21, No. 1, e14560, 01.2025.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes

AU - Thirumalai, Srishruthi

AU - Livesey, Frederick J.

AU - Patani, Rickie

AU - Hung, Christy

PY - 2025/1

Y1 - 2025/1

N2 - 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.© 2025 The Author(s).

AB - 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.© 2025 The Author(s).

KW - Humans

KW - Induced Pluripotent Stem Cells/drug effects

KW - Down Syndrome/metabolism

KW - Astrocytes/drug effects

KW - Mitochondria/drug effects

KW - Amyloid beta-Protein Precursor/genetics

KW - Oligonucleotides, Antisense/pharmacology

KW - Phenotype

KW - Cell Differentiation/drug effects

KW - Alzheimer Disease/metabolism

KW - Cells, Cultured

KW - Superoxides/metabolism

KW - Alzheimer’s disease

KW - antisense oligonucleotides

KW - APP

KW - Down syndrome

KW - mitochondrial function

KW - astrocyte

U2 - 10.1002/alz.14560

DO - 10.1002/alz.14560

M3 - RGC 21 - Publication in refereed journal

C2 - 39877983

SN - 1552-5260

VL - 21

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 1

M1 - e14560

ER -

APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes

Abstract

Research Keywords

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