Short amylin receptor antagonist peptides improve memory deficits in Alzheimer's disease mouse model.

Abstract

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer's disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12-14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY within the peptides is an essential sequence for preservation of the beneficial effects of the fragments that we report here and constitutes a new pharmacological target. These findings suggest that the amylin receptor antagonism may represent a novel therapy for AD.

• Authors: Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 10942 (07 29 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31358858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Islet Amyloid Polypeptide
• Neuroprotective Agents
• Peptide Fragments
• Receptors, Islet Amyloid Polypeptide

Topics

• Alzheimer Disease (drug therapy)
• Animals
• Female
• Hippocampus (drug effects)
• Islet Amyloid Polypeptide (chemistry)
• Long-Term Potentiation
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology, therapeutic use)
• Peptide Fragments (pharmacology, therapeutic use)
• Receptors, Islet Amyloid Polypeptide (antagonists & inhibitors, metabolism)
• Spatial Memory