Lithium modulates multiple tau kinases with distinct effects in cortical and hippocampal neurons according to concentration ranges

Autor(es)

De-Paula, V. J. ^{[1, 2]} ; Forlenza, V, O.

Afiliação do(s) autor(es)

^[1] V, Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Dept & Inst Psiquiatria, Lab Neurociencias LIM 27, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Psiquiatria, Lab Psicobiol LIM 23, Hosp Clin, Fac Med, Rua Dr Ovidio Pires de Campos 785, BR-05403903 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY; v. 395, n. 1 NOV 2021.
• Citações Web of Science: 0

Resumo

The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3 beta), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3 beta activity was determined by the GSK3 beta ratio (rGSK beta). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3 beta activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons. (AU)

• 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: 14/50873-3 - INCT 2014: Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN)
• Beneficiário: Wagner Farid Gattaz
• Modalidade de apoio: Auxílio à Pesquisa - Temático