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Guanosine Neuroprotection of Presynaptic Mitochondrial Calcium Homeostasis in a Mouse Study with Amyloid-β Oligomers

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Abstract

Amyloid-β oligomers (AβOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer’s disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AβOs was used to investigate the toxicity of AβOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AβOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AβOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.

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Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CPNq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Instituto Nacional de Ciência e Tecnologia-Excitotoxicidade e Neuroproteção (INCT-EN), Universidade Federal do Rio Grande do Sul (UFRGS), and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS).

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Authors and Affiliations

  1. Graduate Program in Biological Sciences - Biochemistry. Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul – UFRGS, Porto Alegre, Brazil

    Jussemara Souza da Silva, Yasmine Nonose, Francieli Rohden, Pâmela C. Lukasewicz Ferreira, Fernanda Urruth Fontella, Andréia Rocha, Andressa Wigner Brochier, Rodrigo Vieira Apel, Thais Martins de Lima, Bianca Seminotti, Alexandre Umpierrez Amaral & Diogo O. Souza

  2. Department of Biological Sciences, Integrated Regional University of High Uruguay and Missions – URI, Erechim, Brazil

    Alexandre Umpierrez Amaral

  3. Laboratory of Bioenergetics and Mitochondrial Physiology. Graduate Program in Cellular Biophysics and Biochemistry. Institute of Medical Biochemistry Leopoldo de Meis, Health Sciences Centre, Federal University of Rio de Janeiro – UFRJ, Rio de Janeiro, Brazil

    Antonio Galina

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Contributions

Conceptualization, J.S.S. and D.O.S.; methodology, J.S.S., D.O.S., A.U.A., and A.G; investigation, J.S.S., Y.N., F.R., P.C.L.F., F.U.F., A.S.R, A.W.B., T.M.L., R.V.A., and B.S.; writing (original draft), J.S.S. and D.O.S.; writing (review and editing), J.S.S., D.O.S., Y.N., A.U.A, and A.G.; funding acquisition, D.O.S.; resources, J.S.S. and D.O.S.; and supervision, D.O.S.

Corresponding author

Correspondence to Diogo O. Souza.

Ethics declarations

All animal experiments were performed under the principles of the laboratory of animal care from the National Research Institute and approved by the Federal University of Rio Grande do Sul (UFRGS) Animal Care and Use Committee (CEUA/UFRGS no. 30169).

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The authors declare that they have no conflict of interests.

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da Silva, J.S., Nonose, Y., Rohden, F. et al. Guanosine Neuroprotection of Presynaptic Mitochondrial Calcium Homeostasis in a Mouse Study with Amyloid-β Oligomers. Mol Neurobiol 57, 4790–4809 (2020). https://doi.org/10.1007/s12035-020-02064-4

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