BAG2 expression dictates a functional intracellular switch between the p38-dependent effects of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.
The histopathological hallmarks present in Alzheimer's disease (AD) brain are plaques of Aβ peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the α7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.
Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
Adriele Silva Alves
AS
de Oliveira
Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
Fernando Enrique
FE
Santiago
Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
Laiz Furlan
LF
Balioni
Department of Genetics and Evolutionary Biology, Biosciences Institute, Universidade de São Paulo, São Paulo, SP, Brazil.
Merari de Fatima Ramires
Mde F
Ferrari
Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
Maria Camila
MC
Almeida
Center of Natural and Human Sciences, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil. Electronic address: daniel.carrettiero@ufabc.edu.br.
Daniel Carneiro
DC
Carrettiero
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
C588369:BAG2 protein, rat; D018832:Molecular Chaperones; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins; D009538:Nicotine; D048051:p38 Mitogen-Activated Protein Kinases
Alzheimer's disease; CHRNA7; Hippocampus; Mecamylamine; Methyllycaconitine; Primary cell culture; SB203580; SH-SY5Y