Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation.
Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism.
Neuroscience Post-Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Núbia
N
Broetto
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Fernanda
F
Hansen
Neuroscience Post-Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Giovana
G
Brolese
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Cristiane
C
Batassini
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Franciane
F
Lirio
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Fabiana
F
Galland
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
João Paulo Almeida
JP
Dos Santos
Department of Cellular Biology, Embryology and Genetics, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Márcio Ferreira
MF
Dutra
Neuroscience Post-Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: casg@ufrgs.br.
Carlos-Alberto
CA
Gonçalves
D000818:Animals; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005904:Glial Fibrillary Acidic Protein / Q000134:cerebrospinal fluid; D005947:Glucose / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019319:Okadaic Acid / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D064568:S100 Calcium Binding Protein beta Subunit / Q000134:cerebrospinal fluid / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; C579158:S100b protein, rat; D016875:tau Proteins; D019319:Okadaic Acid; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase; D005978:Glutathione; D005947:Glucose
Alzheimer's disease; GFAP; Glucose uptake; Okadaic acid; S100B; Tau phosphorylation