Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Corrigan, Rachel R.^{a; 1} | Labrador, Luis^{b; #} | Grizzanti, John^{a; 2; #} | Mey, Megan^a | Piontkivska, Helen^c | Casadesús, Gemma^{b; *}

Affiliations: [a] School of Biomedical Sciences, Kent State University, Kent, OH, USA | [b] Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA | [c] Department of Biological Sciences, Kent State University, Kent, OH, USA

Correspondence: [*] Correspondence to: Gemma Casadesús, Department of Pharmacology & Therapeutics, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA. E-mail: gcasadesus@ufl.edu.

Note: [1] Present Address: The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA.

Note: [2] Present Address: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

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

Abstract: Background:Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer’s disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. Objective:Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. Methods:To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. Results:Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. Conclusion:These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

Keywords: Alzheimer’s disease, amylin, amyloid-β, metabolism, receptor antagonism, RNA sequencing

DOI: 10.3233/JAD-221057

Journal: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1495-1514, 2023