Journal of Alzheimer’s Disease 46 (2015) 535–548 DOI 10.3233/JAD-142760 IOS Press 535 Antisense against Amyloid- Protein Precursor Reverses Memory Deficits and Alters Gene Expression in Neurotropic and Insulin-Signaling Pathways in SAMP8 Mice Harvey J. Armbrecht a,b,d,∗ , Akbar M. Siddiqui c , Michael Green c , Susan A. Farr a,b , Vijaya B. Kumar a,b , William A. Banks a,b,f ,1 , Ping Patrick e , Gul N. Shah e and John E. Morley a,b a Geriatric Research, Education and Clinical Center (GRECC), St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA b Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA c Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA d Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA e Division of Endocrinology, Saint Louis University School of Medicine, St. Louis, MO, USA f Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA Handling Associate Editor: D. Allan Butterfield Accepted 4 March 2015 Abstract. The senescence-accelerated mouse (SAMP8) strain exhibits an age-related decrease in memory accompanied by an increase in hippocampal amyloid- protein precursor (APP) and amyloid- peptide (A). We have shown that administration of an antisense oligonucleotide against the A region of APP (APP antisense) reverses the memory deficits. The purpose of this study was to determine the effect of peripheral (IV) administration of APP antisense on hippocampal gene expression. The APP antisense reversed the memory deficits and altered expression of 944 hippocampal genes. Pathway analysis showed significant gene expression changes in nine pathways. These include the MAPK signaling pathway (p = 0.0078) and the phosphatidylinositol signaling pathway (p =0.043), which we have previously shown to be altered in SAMP8 mice. The changes in these pathways contributed to significant changes in the neurotropin (p = 0.0083) and insulin signaling (p = 0.015) pathways, which are known to be important in learning and memory. Changes in these pathways were accompanied by phosphorylation changes in the downstream target proteins p70S6K, GSK3, ERK, and CREB. These changes in hippocampal gene expression and protein phosphorylation may suggest specific new targets for antisense therapy aimed at improving memory. Keywords: Antisense oligonucleotides, gene expression, MAPK signaling, memory loss, phosphatidylinositol signaling, SAMP8 mouse 1 Present address: Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care Sys- tem, Seattle, WA, USA and Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA. ∗ Correspondence to: Harvey J. Armbrecht, PhD, Geriatric Center (11G-JB), St. Louis Veterans Affairs Medical Center, #1 Jefferson Barracks Drive, St. Louis, MO 63125, USA. Tel.: +1 314 894 6511; E-mail: hjarmbrec@aol.com. ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved