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

• 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
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201505846

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.