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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505846 |
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| author | Anthony J Hinrich Francine M Jodelka Jennifer L Chang Daniella Brutman Angela M Bruno Clark A Briggs Bryan D James Grace E Stutzmann David A Bennett Steven A Miller Frank Rigo Robert A Marr Michelle L Hastings |
| author_facet | Anthony J Hinrich Francine M Jodelka Jennifer L Chang Daniella Brutman Angela M Bruno Clark A Briggs Bryan D James Grace E Stutzmann David A Bennett Steven A Miller Frank Rigo Robert A Marr Michelle L Hastings |
| author_sort | Anthony J Hinrich |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-53d79b4ef2ba4429a49c1630f225c643 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-53d79b4ef2ba4429a49c1630f225c6432025-08-20T03:46:25ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-02-018432834510.15252/emmm.201505846Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotidesAnthony J Hinrich0Francine M Jodelka1Jennifer L Chang2Daniella Brutman3Angela M Bruno4Clark A Briggs5Bryan D James6Grace E Stutzmann7David A Bennett8Steven A Miller9Frank Rigo10Robert A Marr11Michelle L Hastings12Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceDepartment of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceDepartment of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceDepartment of Biology, Lake Forest CollegeDepartment of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceDepartment of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceRush Alzheimer's Disease Center, Rush University Medical CenterDepartment of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceRush Alzheimer's Disease Center, Rush University Medical CenterDepartment of Psychology, College of Health Professions, Rosalind Franklin University of Medicine and ScienceIonis PharmaceuticalsDepartment of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceDepartment of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and ScienceAbstract 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.https://doi.org/10.15252/emmm.201505846Alzheimer's diseaseAntisense oligonucleotidesApoER2SplicingTherapeutics |
| spellingShingle | Anthony J Hinrich Francine M Jodelka Jennifer L Chang Daniella Brutman Angela M Bruno Clark A Briggs Bryan D James Grace E Stutzmann David A Bennett Steven A Miller Frank Rigo Robert A Marr Michelle L Hastings Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides EMBO Molecular Medicine Alzheimer's disease Antisense oligonucleotides ApoER2 Splicing Therapeutics |
| title | Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides |
| title_full | Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides |
| title_fullStr | Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides |
| title_full_unstemmed | Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides |
| title_short | Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides |
| title_sort | therapeutic correction of apoer2 splicing in alzheimer s disease mice using antisense oligonucleotides |
| topic | Alzheimer's disease Antisense oligonucleotides ApoER2 Splicing Therapeutics |
| url | https://doi.org/10.15252/emmm.201505846 |
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