title: Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides.
abstract: 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.
authors.affiliation: Department of Cell Biology and Anatomy, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hinrich
authors.affiliation: Department of Cell Biology and Anatomy, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Francine M
authors.initials: FM
authors.lastname: Jodelka
authors.affiliation: Department of Cell Biology and Anatomy, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Chang
authors.affiliation: Department of Biology, Lake Forest College, Lake Forest, IL, USA.
authors.forename: Daniella
authors.initials: D
authors.lastname: Brutman
authors.affiliation: Department of Neuroscience, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bruno
authors.affiliation: Department of Neuroscience, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: James
authors.affiliation: Department of Neuroscience, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Stutzmann
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Psychology, College of Health Professions Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Miller
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Neuroscience, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Marr
authors.affiliation: Department of Cell Biology and Anatomy, Chicago Medical School Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA michelle.hastings@rosalindfranklin.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D012326:RNA Splicing; D016896:Treatment Outcome
chemical_list: D026502:LDL-Receptor Related Proteins; D016376:Oligonucleotides, Antisense; C098773:low density lipoprotein receptor-related protein 8
keywords: Alzheimer's disease; Antisense oligonucleotides; ApoER2; Splicing; Therapeutics