Neuroprotective Effects of the Amylin Analog, Pramlintide, on Alzheimer’s Disease Are Associated with Oxidative Stress Regulation Mechanisms

Article type: Research Article

Authors: Patrick, Sarah^a | Corrigan, Rachel^{a; 1} | Grizzanti, John^{a; 1} | Mey, Megan^a | Blair, Jeff^a | Pallas, Merce^c | Camins, Antonio^c | Lee, Hyoung-gon^b | Casadesus, Gemma^{a; d; *}

Affiliations: [a] School of Biomedical Sciences, Kent State University, Kent, OH, USA | [b] Department of Biology, The University of Texas San Antonio, San Antonio, TX, USA | [c] Facultat de Farmacia, Universitat de Barcelona, Barcelona, Spain | [d] Department of Biological Sciences, Kent State University, Kent, OH, USA

Correspondence: [*] Correspondence to: Gemma Casadesus Smith, PhD, Department of Biological Sciences, Kent State University, 256 Cunningham Hall, Kent, OH 44240, USA. Tel.: +1 330 672 7894; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Administration of the recombinant analog of the pancreatic amyloid amylin, Pramlintide, has shown therapeutic benefits in aging and Alzheimer’s disease (AD) models, both on cognition and amyloid-β (Aβ) pathology. However, the neuroprotective mechanisms underlying the benefits of Pramlintide remain unclear. Given the early and critical role of oxidative stress in AD pathogenesis and the known reactive oxygen species (ROS) modulating function of amyloids, we sought to determine whether Pramlintide’s neuroprotective effects involve regulation of oxidative stress mechanisms. To address this, we treated APP/PS1 transgenic mice with Pramlintide for 3 months, starting at 5.5 months prior to widespread AD pathology onset, and measured cognition (Morris Water Maze), AD pathology, and oxidative stress-related markers and enzymes in vivo. In vitro, we determined the ability of Pramlintide to modulate H2O2-induced oxidative stress levels. Our data show that Pramlintide improved cognitive function, altered amyloid-processing enzymes, reduced plaque burden in the hippocampus, and regulated endogenous antioxidant enzymes (MnSOD and GPx1) and the stress marker HO-1 in a location specific manner. In vitro, Pramlintide treatment in neuronal models reduced H2O2-induced endogenous ROS production and lipid peroxidation in a dose-dependent manner. Together, these results indicate that Pramlintide’s benefits on cognitive function and pathology may involve antioxidant-like properties of this compound.

Keywords: Alzheimer’s disease, amylin, metabolism, neuroprotection, oxidative stress, pramlintide

DOI: 10.3233/JAD-180421

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 157-168, 2019