Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides

Apolipoprotein E receptor 2 ( ApoER2 ) is an apolipoprotein E receptor involved in long‐term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for th...

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Published in:	EMBO molecular medicine Vol. 8; no. 4; pp. 328 - 345
Main Authors:	Hinrich, Anthony J, Jodelka, Francine M, Chang, Jennifer L, Brutman, Daniella, Bruno, Angela M, Briggs, Clark A, James, Bryan D, Stutzmann, Grace E, Bennett, David A, Miller, Steven A, Rigo, Frank, Marr, Robert A, Hastings, Michelle L
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2016 EMBO Press John Wiley and Sons Inc Springer Nature
Subjects:	Alternative splicing Alzheimer Disease - drug therapy Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Animal cognition Animals Antisense oligonucleotides ApoER2 Apolipoprotein E Apolipoproteins Binding sites Brain Brain - physiology Cognition Cognitive ability Disease Models, Animal Drug dosages EMBO27 EMBO28 Humans Kinases LDL-Receptor Related Proteins - genetics LDL-Receptor Related Proteins - metabolism Learning Ligands Memory Mice Mice, Transgenic Neurodegeneration Neurodegenerative diseases Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - therapeutic use Peptides Phosphorylation Potentiation Proteins Research Article RNA Splicing Splicing Therapeutics Transgenic mice Treatment Outcome Variance analysis Antisense oligonucleotides Splicing Alzheimer's disease ApoER2 Therapeutics
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Summary:	Apolipoprotein E receptor 2 ( ApoER2 ) is an apolipoprotein E receptor involved in long‐term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for the receptor in the disease is not clear. ApoER2 signaling requires amino acids encoded by alternatively spliced exon 19. Here, we report that the balance of ApoER2 exon 19 splicing is deregulated in postmortem brain tissue from AD patients and in a transgenic mouse model of AD. To test the role of deregulated ApoER2 splicing in AD, we designed an antisense oligonucleotide (ASO) that increases exon 19 splicing. Treatment of AD mice with a single dose of ASO corrected ApoER2 splicing for up to 6 months and improved synaptic function and learning and memory. These results reveal an association between ApoER2 isoform expression and AD, and provide preclinical evidence for the utility of ASOs as a therapeutic approach to mitigate Alzheimer's disease symptoms by improving ApoER2 exon 19 splicing. Synopsis ApoER2 splicing is deregulated in Alzheimer's disease (AD) patients and mouse models of AD. Correcting this splicing defect using antisense oligonucleotides (ASOs) improves synaptic function, learning, and memory in mice, suggesting ApoER2 ASOs as a promising therapeutic strategy against AD. ApoER2 alternative splicing is deregulated in Alzheimer's disease. ASOs directed against ApoER2 correct the deregulated alternative splicing. ASO‐mediated correction of ApoER2 splicing improves synaptic strength and cognition in AD mice. Graphical Abstract ApoER2 splicing is deregulated in Alzheimer's disease (AD) patients and mouse models of AD. Correcting this splicing defect using antisense oligonucleotides (ASOs) improves synaptic function, learning and memory in mice, suggesting ApoER2 ASOs as a promising therapeutic strategy against AD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 See also: CR Wasser & J Herz (April 2016)
ISSN:	1757-4676 1757-4684
DOI:	10.15252/emmm.201505846