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Calcineurin-Mediated Hippocampal Inflammatory Alterations in Streptozotocin-Induced Model of Dementia

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Abstract

Although the pathogenesis of Alzheimer’s disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of β-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca2+/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1 week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48 kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4 weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.

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Acknowledgments

This study was supported by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazil), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS), and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN).

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  1. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-003, Brazil

    João Paulo Almeida dos Santos, Adriana Fernanda Vizuete & Carlos-Alberto Gonçalves

  2. Lab Calcium Binding Proteins in CNS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 – Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil

    João Paulo Almeida dos Santos, Adriana Fernanda Vizuete & Carlos-Alberto Gonçalves

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dos Santos, J.P.A., Vizuete, A.F. & Gonçalves, CA. Calcineurin-Mediated Hippocampal Inflammatory Alterations in Streptozotocin-Induced Model of Dementia. Mol Neurobiol 57, 502–512 (2020). https://doi.org/10.1007/s12035-019-01718-2

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