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Title: Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer's Disease Mouse Models.
Austin Authors: Patel, Aarti;Kimura, Ryoichi;Fu, Wen;Soudy, Rania;MacTavish, David;Westaway, David;Yang, Jing;Davey, Rachel A;Zajac, Jeffrey D ;Jhamandas, Jack H
Affiliation: Center for Liberal Arts and Sciences, Sanyo-Onoda City University, Yamaguchi , 756-0884, Japan
Faculty of Pharmacy, Cairo University, Giza, Egypt
Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, T6G 2M8, Canada
Medicine (University of Melbourne)
Department of Medicine (Neurology), Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada
Issue Date: Oct-2021
Date: 2021-07-27
Publication information: Molecular neurobiology 2021-10; 58(10): 5369-5382
Abstract: Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer's disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.
DOI: 10.1007/s12035-021-02490-y
ORCID: 0000-0002-4688-6500
Journal: Molecular Neurobiology
PubMed URL: 34312771
Type: Journal Article
Subjects: Alzheimer’s disease
Amylin receptor
Amyloid-β protein
Calcitonin receptor
Long-term potentiation
Spatial memory
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