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Atorvastatin Improves Mitochondrial Function and Prevents Oxidative Stress in Hippocampus Following Amyloid-β1–40 Intracerebroventricular Administration in Mice

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Abstract

Amyloid-β (Aβ) peptides play a significant role in the pathogenesis of Alzheimer’s disease (AD). Neurotoxic effects promoted by Aβ peptides involve glutamate transmission impairment, decrease of neurotrophic factors, mitochondrial dysfunction, oxidative stress, synaptotoxicity, and neuronal degeneration. Here, we assessed the early events evoked by Aβ1–40 on the hippocampus. Additionally, we sought to unravel the molecular mechanisms of atorvastatin preventive effect on Aβ-induced hippocampal damage. Mice were treated orally (p.o.) with atorvastatin 10 mg/kg/day during 7 consecutive days before the intracerebroventricular (i.c.v.) infusion of Aβ1–40 (400 pmol/site). Twenty-four hours after Aβ1–40 infusion, a reduced content of mature BDNF/proBDNF ratio was observed in Aβ-treated mice. However, there is no alteration in synaptophysin, PSD-95, and doublecortin immunocontent in the hippocampus. Aβ1–40 promoted an increase in reactive oxygen species (ROS) and nitric oxide (NO) generation in hippocampal slices, and atorvastatin prevented this oxidative burst. Mitochondrial OXPHOS was measured by high-resolution respirometry. At this time point, Aβ1–40 did not alter the O2 consumption rates (OCR) related to phosphorylating state associated with complexes I and II, and the maximal OCR. However, atorvastatin increased OCR of phosphorylating state associated with complex I and complexes I and II, maximal OCR of complexes I and II, and OCR associated with mitochondrial spare capacity. Atorvastatin treatment improved mitochondrial function in the rodent hippocampus, even after Aβ infusion, pointing to a promising effect of improving brain mitochondria bioenergetics. Therefore, atorvastatin could act as an adjuvant in battling the symptoms of AD to preventing or delaying the disease progression.

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Abbreviations

Aβ:

Amyloid-beta

Aβ1–40 :

Amyloid-beta1–40 peptide

AD:

Alzheimer’s disease

Ator:

Atorvastatin

BDNF:

Brain-derived neurotrophic factor

ETS:

Electron transport system

HMG-CoA:

hydroxy-methylglutaryl-CoA

i.c.v.:

Intracerebroventricular

NMDA:

N-methyl-D-aspartate

NO:

Nitric oxide

NOS2:

Inducible nitric oxide synthase

OCR:

Oxygen consumption rate

OXPHOS:

Mitochondrial oxidative phosphorylation

Δψmit:

Mitochondrial membrane potential

PSD-95:

Postsynaptic protein of 95 kDaltons

ROS:

Reactive oxygen species.

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Funding

This research is supported by grants from the Brazilian funding agencies: FAPESC (Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) – INCT for Excitotoxicity and Neuroprotection; Universal 401065/2014-6; CNPq Productivity Fellowship. G.M. is recipient of post-doctoral fellowship from CNPq (154859/2018-4), and W.C.M. was recipient of a PhD fellowship from CAPES.

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Author notes

  1. Gianni Mancini and Wagner C. Martins contributed equally to this work.

Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    Gianni Mancini, Wagner C. Martins, Andreza Fabro de Bem & Carla I. Tasca

  2. Programa de Pós-Graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Gianni Mancini, Jade de Oliveira, Andreza Fabro de Bem & Carla I. Tasca

  3. Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Wagner C. Martins & Carla I. Tasca

  4. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Jade de Oliveira

  5. Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, Brazil

    Andreza Fabro de Bem

Authors
  1. Gianni Mancini
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  2. Wagner C. Martins
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  3. Jade de Oliveira
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  4. Andreza Fabro de Bem
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  5. Carla I. Tasca
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Corresponding author

Correspondence to Carla I. Tasca.

Ethics declarations

Experiments followed the “Principles of Laboratory Animal Care” (NIH 2011) and approved by the Ethic Committee on Animal Use of the Federal University of Santa Catarina (CEUA/UFSC PP00955).

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The financial support agencies had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Mancini, G., Martins, W.C., de Oliveira, J. et al. Atorvastatin Improves Mitochondrial Function and Prevents Oxidative Stress in Hippocampus Following Amyloid-β1–40 Intracerebroventricular Administration in Mice. Mol Neurobiol 57, 4187–4201 (2020). https://doi.org/10.1007/s12035-020-02026-w

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  • DOI: https://doi.org/10.1007/s12035-020-02026-w

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