Antisense against Amyloid-β Protein Precursor Reverses Memory Deficits and Alters Gene Expression in Neurotropic and Insulin-Signaling Pathways in SAMP8 Mice

Article type: Research Article

Authors: Armbrecht, Harvey J.^{a; b; d; *} | Siddiqui, Akbar M.^c | Green, Michael^c | Farr, Susan A.^{a; b} | Kumar, Vijaya B.^{a; b} | Banks, William A.^{a; b; f; 1} | Patrick, Ping^e | Shah, Gul N.^e | Morley, John E.^{a; b}

Affiliations: [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

Correspondence: [*] 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; [email protected]

Note: [1] Present address: Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA and Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.

Abstract: The senescence-accelerated mouse (SAMP8) strain exhibits an age-related decrease in memory accompanied by an increase in hippocampal amyloid-β protein precursor (AβPP) and amyloid-β peptide (Aβ). We have shown that administration of an antisense oligonucleotide against the Aβ region of AβPP (AβPP antisense) reverses the memory deficits. The purpose of this study was to determine the effect of peripheral (IV) administration of AβPP antisense on hippocampal gene expression. The AβPP 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, GSK3β, 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

DOI: 10.3233/JAD-142760

Journal: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 535-548, 2015