Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease

Stephanie R. Murphy; Catherine C.Y. Chang; Godwin Dogbevia; Elena Y. Bryleva; Zachary Bowen; Mazahir T. Hasan; Ta Yuan Chang

doi:10.1038/mt.2013.118

Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease

Stephanie R. Murphy, Catherine C.Y. Chang, Godwin Dogbevia, Elena Y. Bryleva, Zachary Bowen, Mazahir T. Hasan, Ta Yuan Chang^*

^*Corresponding author for this work

Institute of Experimental and Clinical Pharmacology and Toxicology

97 Citations (Scopus)

Abstract

Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.

Original language	English
Journal	Molecular Therapy
Volume	21
Issue number	8
Pages (from-to)	1497-1506
Number of pages	10
ISSN	1525-0016
DOIs	https://doi.org/10.1038/mt.2013.118
Publication status	Published - 01.01.2013

Funding

We thank Charles Barlowe (Dartmouth) and Maximillian Rogers (Dartmouth) for helpful discussion about this project; Henry Higgs (Dartmouth) for helpful discussion and provision of mouse 3T3 fibroblasts; Ronald Taylor (Dartmouth) for providing us with SURE Escherichia coli; and Alireza Kheirolla (Dartmouth) for assistance with the mouse surgery. This work was supported by National Institutes of Health grant AG37609 to T.-Y.C. and by grants from Max Planck Society and the Fritz Thyssen Stiftung to M.T.H. S.R.M. received additional support from the National Institute of General Medical Sciences Award #T32GM008704. The authors declared no conflict of interest.

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mt.2013.118

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title = "Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease",

abstract = "Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.",

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AU - Chang, Ta Yuan

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Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease

Abstract

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