2. Academic Validation
  3. Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease

Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease

  • Alzheimers Dement (N Y). 2016 Dec 10;3(1):44-56. doi: 10.1016/j.trci.2016.11.005.
Rania Soudy 1 2,  Aarti Patel 1,  Wen Fu 1,  Kamaljit Kaur 3 4,  David MacTavish 1,  David Westaway 1 5 6,  Rachel Davey 7,  Jeffrey Zajac 7,  Jack Jhamandas 1
Affiliations

Affiliations

  • 1 Department of Medicine (Neurology), Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
  • 2 Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 3 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
  • 4 Chapman University School of Pharmacy, Irvine, California, USA.
  • 5 Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
  • 6 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
  • 7 Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
PMID: 29067318 DOI: 10.1016/j.trci.2016.11.005
Abstract

Introduction: Amylin Receptor serves as a portal for the expression of deleterious effects of amyloid β-protein (Aβ), a key pathologic hallmark of Alzheimer's disease. Previously, we showed that AC253, an Amylin Receptor Antagonist, is neuroprotective against Aβ toxicity in vitro and abrogates Aβ-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 disease-modifying therapy for this condition.

Keywords

AC253 peptide; Alzheimer's disease; Amylin receptor; Amyloid β; Brain penetration; In vivo imaging.

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