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Chronic administration of Tat-GluR23Y ameliorates cognitive dysfunction targeting CREB signaling in rats with amyloid beta neurotoxicity

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Abstract

Alzheimer’s disease (AD) is behaviorally characterized by memory impairments, and pathologically by amyloid β1–42 (Aβ1–42) plaques and tangles. Aβ binds to excitatory synapses and disrupts their transmission due to dysregulation of the glutamate receptors. Here we hypothesized that chronic inhibition of the endocytosis of AMPA receptors together with GluN2B subunit of NMDA receptors might improve cognition deficit induced by Aβ(1–42) neurotoxicity. Forty male Wistar rats were used in this study and divided into 5 groups: Saline + Saline, Aβ+Saline, Aβ+Ifen (Ifenprodil, 3 nmol /2 weeks), Aβ+GluR23Y (Tat-GluR23Y 3 μmol/kg/2 weeks) and Aβ+Ifen+GluR23Y (same doses and durations). Aβ(1–42) neurotoxicity was induced by intracerebroventricular (ICV) injection of Aβ1–42 (2 μg/μl/side), and then animals received the related treatments for 14 days. Cognitive performance of rats and hippocampal level of cAMP-response element-binding (CREB) were evaluated using Morris Water Maze (MWM), and western blotting respectively. Obtained data from the acquisition trials were analyzed by two way Anova and Student T test. Also one way Analysis of variance (ANOVA) with post hoc Tuckey were used to clarify between groups differences in probe test. The Group receiving Aβ, showed significant cognition deficit (long latency to platform and short total time spent in target quadrant (TTS), parallel with lower level of hippocampal CREB, versus vehicle group. While, Aβ+ GluR23Y exhibited the shortest latency to platform and the longest TTS during the probe test, parallel with the higher hippocampal level of CREB compared with other groups. The present study provides evidence that chronic administration of Tat-GluR23Y; an inhibitor of GluA2-AMPARs endocytosis, successfully restores spatial memory impaired by amyloid beta neurotoxicity targeting CREB signaling pathway.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Authors would like to thank Dr. Bahram Soltani, head of Cellular & Molecular Research Center and department of pharmacology, Faculty of medicine, Rasht, Iran for their laboratory facilities and technical support.

Funding

This work was a master science student thesis and financially was supported by the grant (No IR.GUMS.REC.1396.264) from Research deputy of Guilan University of Medical Sciences, Rasht, Iran.

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Authors and Affiliations

  1. Cellular & Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, 8th Km of Rasht –Tehran road, Guilan University Complex, Rasht, Guilan, 41996-13769, Iran

    Fatemeh Ashourpour & Parvin Babaei

  2. Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Fatemeh Ashourpour & Parvin Babaei

  3. Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Fatemeh Ashourpour, Adele Jafari & Parvin Babaei

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  1. Fatemeh Ashourpour
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  2. Adele Jafari
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  3. Parvin Babaei
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PB designed the study, and interpreted data, had a major contribution in writing and revising the manuscript. FA performed experiment, drafted the manuscript and analyzed data. AJ interpreted western blot data. All authors read and approved the final manuscript.

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Correspondence to Parvin Babaei.

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Ashourpour, F., Jafari, A. & Babaei, P. Chronic administration of Tat-GluR23Y ameliorates cognitive dysfunction targeting CREB signaling in rats with amyloid beta neurotoxicity. Metab Brain Dis 36, 701–709 (2021). https://doi.org/10.1007/s11011-020-00662-8

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