Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice
Affiliations: [a] Research and Development Service, VA Medical Center, St. Louis, MO, USA | [b] Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, MO, USA | [c] Geriatric Research Educational and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA | [d] Department of Internal Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA, USA | [e] Department of Internal Medicine, Division of Endocrinology, St. Louis University School of Medicine, St. Louis, MO, USA
Correspondence:
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Correspondence to: Susan A. Farr, PhD, St. Louis University School of Medicine/VA Medical Center St. Louis, 915 North Grand Blvd. 151/JC, St. Louis, MO 63106, USA. E-mail: farrsa@slu.edu.
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.
