Neuronal-Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer's Disease: Gene Ontology and Lithium Pathways

Autor(es)

Rocha, Nicole Kemberly R. ^[1] ; Themoteo, Rafael ^[2] ; Brentani, Helena ^[1] ; Forlenza, Orestes V. ^[2] ; De Paula, Vanessa De Jesus Rodrigues ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Psicobiol LIM2, Dept & Inst Psiquiatria, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Neurociencias LIM27, Dept Inst & Psiquiatria, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN NEUROSCIENCE; v. 14, DEC 1 2020.
• Citações Web of Science: 0

Resumo

Neuronal-glial interactions are critical for brain homeostasis, and disruption of this process may lead to excessive glial activation and inadequate pro-inflammatory responses. Abnormalities in neuronal-glial interactions have been reported in the pathophysiology of Alzheimer's disease (AD), where lithium has been shown to exert neuroprotective effects, including the up-regulation of cytoprotective proteins. In the present study, we characterize by Gene Ontology (GO) the signaling pathways related to neuronal-glial interactions in response to lithium in a triple-transgenic mouse model of AD (3x-TgAD). Mice were treated for 8 months with lithium carbonate (Li) supplemented to chow, using two dose ranges to yield subtherapeutic working concentrations (Li1, 1.0 g/kg; and Li2, 2.0 g/kg of chow), or with standard chow (Li0). The hippocampi were removed and analyzed by proteomics. A neuronal-glial interaction network was created by a systematic literature search, and the selected genes were submitted to STRING, a functional network to analyze protein interactions. Proteomics data and neuronal-glial interactomes were compared by GO using ClueGo (Cytoscape plugin) with p <= 0.05. The proportional effects of neuron-glia interactions were determined on three GO domains: (i) biological process; (ii) cellular component; and (iii) molecular function. The gene ontology of this enriched network of genes was further stratified according to lithium treatments, with statistically significant effects observed in the Li2 group (as compared to controls) for the GO domains biological process and cellular component. In the former, there was an even distribution of the interactions occurring at the following functions: ``positive regulation of protein localization to membrane,{''} ``regulation of protein localization to cell periphery,{''} ``oligodendrocyte differentiation,{''} and ``regulation of protein localization to plasma membrane.{''} In cellular component, interactions were also balanced for ``myelin sheath{''} and ``rough endoplasmic reticulum.{''} We conclude that neuronal-glial interactions are implicated in the neuroprotective response mediated by lithium in the hippocampus of AD-transgenic mice. The effect of lithium on homeostatic pathways mediated by the interaction between neurons and glial cells are implicated in membrane permeability, protein synthesis and DNA repair, which may be relevant for the survival of nerve cells amidst AD pathology. (AU)

• Processo FAPESP: 17/14418-8 - Efeito do lítio sobre o tamanho telomérico em neurônios corticais e hipocampais tratados com beta amiloide
• Beneficiário: Rafael Martins Themoteo
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 11/19892-3 - Efeitos do lítio sobre a expressão e atividade das enzimas Fosfolipase A2 e glicogênio sintase quinase 3B e sua relação com o estado de fosforilação da proteína Tau
• Beneficiário: Vanessa de Jesus Rodrigues de Paula
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/01302-9 - Identificação das vias direta e indireta da inibição da glicogênio sintase kinase 3B pelo lítio em cultura de neurônios
• Beneficiário: Vanessa de Jesus Rodrigues de Paula
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 09/52825-8 - Neurobiologia da doença de Alzheimer: marcadores de risco, prognóstico e resposta terapêutica
• Beneficiário: Wagner Farid Gattaz
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/08621-8 - Influência do lítio na interação neurônio-glia em neurônios hipocampais
• Beneficiário: Nicole Kemberly Ribeiro Rocha
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 14/50873-3 - INCT 2014: Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN)
• Beneficiário: Wagner Farid Gattaz
• Modalidade de apoio: Auxílio à Pesquisa - Temático