Cyclic AC253, A Novel Amylin Receptor Antagonist, Improves Cognitive Deficits in a Mouse Model of Alzheimer’s Disease

Authors

Rania Soudy, University of Alberta
Aarti Patel, University of Alberta
Wen Fu, University of Alberta
Kamaljit Kaur, Chapman UniversityFollow
David MacTavish, University of Alberta
David Westaway, University of Alberta
Rachel Davey, University of Melbourne
Jeffrey Zajac, University of Melbourne
Jack Jhamandas, University of Alberta

Document Type

Article

Publication Date

1-2017

Abstract

Introduction: Amylin receptor serves as a portal for the expression of deleterious effects of amyloid b-protein (Ab), a key pathologic hallmark of Alzheimer’s disease. Previously, we showed that AC253, an amylin receptor antagonist, is neuroprotective against Ab toxicity in vitro and abrogates Ab-induced impairment of hippocampal long-term potentiation.

Methods: Amyloid precursor protein–overexpressing TgCRND8 mice received intracerebroventricularly AC253 for 5 months. New cyclized peptide cAC253 was synthesized and administered intraperitoneally three times a week for 10 weeks in the same mouse model. Cognitive functions were monitored, and pathologic changes were quantified biochemically and immunohistochemically.

Results: AC253, when administered intracerebroventricularly, improves spatial memory and learning, increases synaptic integrity, reduces microglial activation without discernible adverse effects in TgCRND8 mice. cAC253 demonstrates superior brain permeability, better proteolytic stability, and enhanced binding affinity to brain amylin receptors after a single intraperitoneal injection. Furthermore, cAC253 administered intraperitoneally also demonstrates improvement in spatial memory in TgCRND8 mice.

Discussion: Amylin receptor is a therapeutic target for Alzheimer’s disease and represents a diseasemodifying therapy for this condition.

Comments

This article was originally published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, volume 3, issue 1, in 2017. DOI: 10.1016/j.trci.2016.11.005

Recommended Citation

Soudy R, Patel A, Fu W, et al. Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer’s disease. Alzheimers Dement (N Y). 2017;3(1):44–56. doi: 10.1016/j.trci.2016.11.005

Copyright

The authors

Creative Commons License

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