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.
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.
authors.affiliation: Research and Development Service, VA Medical Center, St. Louis, MO, USA Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.affiliation: Geriatric Research Educational and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA Department of Internal Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Erickson
authors.affiliation: Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.affiliation: Geriatric Research Educational and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA Department of Internal Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, MO, USA Department of Internal Medicine, Division of Endocrinology, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D020320:Oligoribonucleotides, Antisense
keywords: Antisense oligonucleotide; T-maze; Tg2576; blood brain barrier; cytokines; learning; memory; object recognition; oxidative stress