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. 2014;40(4):1005-16.
doi: 10.3233/JAD-131883.

Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice

Susan A Farr  1 , Michelle A Erickson  2 , Michael L Niehoff  3 , William A Banks  2 , John E Morley  4
Affiliations

Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice

Susan A Farr et al. J Alzheimers Dis. 2014.

Abstract

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.

Keywords: Antisense oligonucleotide; T-maze; Tg2576; blood brain barrier; cytokines; learning; memory; object recognition; oxidative stress.

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Figures

Figure 1
Figure 1
Tg2576 mice administered OL-1 antisense ICV had improved acquisition and retention compared to the Tg2576 mice that received RA. The Tg2576 mice that received OL-1 were not different from the wild type (WT) controls. The numbers per group were Tg2576 RA = 10, Tg2576 Ol-1 = 11 and WT RA = 11. The ** indicates P<0.001.
Figure 2
Figure 2
OL-1 administered via tail vein hadimproved acquisition and retention in Tg2576 mice compared to the Tg2576 mice that received RA (A&B). The Tg2576 mice that received OL-1 had improved retention in object recognition compared to the Tg2576 mice that received RA (C). The discrimination index is determined by dividing the time exploring the novel object divided by the total exploration time of both objects multiplied by 100. The numbers per group were Tg2576 RA = 8, Tg2576 OL-1 = 10 and WT RA = 10. The * indicates P<0.05 and the ** indicates P<0.01.
Figure 3
Figure 3
OL-1 administered via tail vein reduced APP protein levels in Tg2576 mice. Protein expression of APP was measured by dot blot, and analyzed by one-way ANOVA and Newman-Keulsmultiple-comparisons test: *P<0.05, ***P<0.001 vs. RA Tg2576, ###P<0.001 vs. WT RA, n=6–8 per group.
Figure 4
Figure 4
Effects of OL-1 administered via tail vein 3 times at 2 week intervals on soluble (A–C), total (D–F), and the ratio of soluble/total (G–H) Aβ. Aβ levels were measured by ELISA, and analyzed by one-way ANOVA and Newman-Keuls multiple-comparisons test: **P<0.01, ***P<0.001 vs. RA Tg2576; ###P<0.001 vs. WT RA, n=6–8 per group.
Figure 5
Figure 5
Effects of OL-1 administered via tail vein 3 times at 2 week intervals on cytokine and chemokine levels in the CNS. Cytokine and chemokine levels were quantified in brain homogenates using a bead-based multiplex ELISA. All detectable analytes are shown. Data were analyzed by one-way ANOVA and Bonferroni multiple-comparisons test: *P<0.05 vs. RA Tg2576; #P<0.05, ##P<0.01 vs. WT RA, n=6–8 per group.
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