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

Authors: Farr, Susan A; Erickson, Michelle A; Niehoff, Michael L; Banks, William A; Morley, John E

Published In 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.

PubMed ID: 24577464

MeSH Terms: Amyloid beta-Peptides/metabolism; Amyloid beta-Protein Precursor/chemistry*; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism*; Analysis of Variance; Animals; Cytokines/metabolism*; Disease Models, Animal; Drug Administration Routes; Exploratory Behavior/drug effects; Gene Expression Regulation/drug effects; Gene Expression Regulation/genetics; Humans; Learning Disorders/drug therapy*; Learning Disorders/genetics; Male; Maze Learning/drug effects; Memory Disorders/drug therapy*; Memory Disorders/genetics; Mice; Mice, Transgenic; Oligoribonucleotides, Antisense/administration & dosage*; Oxidative Stress/drug effects