Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid-β protein precursor (AβPP) that can decrease AβPP expression and amyloid-β protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress, and restores brain-to-blood efflux of Aβ in SAMP8 mice. Here, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. We administered the OL-1 antisense into the lateral ventricle 3 times at 2week intervals. Seventy-two hours after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with OL-1 antisense 3 times at 2-week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze, novel object recognition, and elevated plus maze. At the end of behavioral testing, brain tissue was collected. OL-1 antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. OL-1 antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze, the mice which received OL-1 antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Journal of Alzheimer's disease : JAD - 40(2014), 4 vom: 01., Seite 1005-16 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Farr, Susan A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.01.2015 Date Revised 21.10.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.3233/JAD-131883 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM235924296 |
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| 100 | 1 | |a Farr, Susan A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice |
| 264 | 1 | |c 2014 | |
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| 500 | |a Date Completed 06.01.2015 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Alzheimer's disease (AD) is a progressive neurodegenerative disease. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid-β protein precursor (AβPP) that can decrease AβPP expression and amyloid-β protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress, and restores brain-to-blood efflux of Aβ in SAMP8 mice. Here, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. We administered the OL-1 antisense into the lateral ventricle 3 times at 2week intervals. Seventy-two hours after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with OL-1 antisense 3 times at 2-week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze, novel object recognition, and elevated plus maze. At the end of behavioral testing, brain tissue was collected. OL-1 antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. OL-1 antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze, the mice which received OL-1 antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Antisense oligonucleotide | |
| 650 | 4 | |a T-maze | |
| 650 | 4 | |a Tg2576 | |
| 650 | 4 | |a blood brain barrier | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a learning | |
| 650 | 4 | |a memory | |
| 650 | 4 | |a object recognition | |
| 650 | 4 | |a oxidative stress | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Amyloid beta-Protein Precursor |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Oligoribonucleotides, Antisense |2 NLM | |
| 700 | 1 | |a Erickson, Michelle A |e verfasserin |4 aut | |
| 700 | 1 | |a Niehoff, Michael L |e verfasserin |4 aut | |
| 700 | 1 | |a Banks, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Morley, John E |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:40 |g year:2014 |g number:4 |g day:01 |g pages:1005-16 |
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