Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine ("Ecstasy").
3,4-Methylenedioxymethamphetamine (MDMA) ("Ecstasy") produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. We examined whether MDMA induces increases in tau protein phosphorylation, which are typically associated with Alzheimer's disease and other chronic neurodegenerative disorders. We injected mice with MDMA at cumulative doses of 10-50 mg/kg intraperitoneally, which are approximately equivalent to doses generally consumed by humans. MDMA enhanced the formation of reactive oxygen species and induced reactive gliosis in the hippocampus, without histological evidence of neuronal loss. An acute or 6 d treatment with MDMA increased tau protein phosphorylation in the hippocampus, revealed by both anti-phospho(Ser(404))-tau and paired helical filament-1 antibodies. This increase was restricted to the CA2/CA3 subfields and lasted 1 and 7 d after acute and repeated MDMA treatment, respectively. Tau protein was phosphorylated as a result of two nonredundant mechanisms: (1) inhibition of the canonical Wnt (wingless-type MMTV integration site family) pathway, with ensuing activation of glycogen synthase kinase-3beta; and (2) activation of type-5 cyclin-dependent kinase (Cdk5). MDMA induced the expression of the Wnt antagonist, Dickkopf-1, and the expression of the Cdk5-activating protein, p25. In addition, the increase in tau phosphorylation was attenuated by strategies that rescued the Wnt pathway or inhibited Cdk5. Finally, an impairment in hippocampus-dependent spatial learning was induced by doses of MDMA that increased tau phosphorylation, although the impairment outlasted this biochemical event. We conclude that tau hyperphosphorylation in the hippocampus may contribute to the impairment of learning and memory associated with MDMA abuse.
Busceti
Carla L
CL
Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
Biagioni
Francesca
F
Riozzi
Barbara
B
Battaglia
Giuseppe
G
Storto
Marianna
M
Cinque
Carlo
C
Molinaro
Gemma
G
Gradini
Roberto
R
Caricasole
Andrea
A
Canudas
Anna Maria
AM
Bruno
Valeria
V
Nicoletti
Ferdinando
F
Fornai
Francesco
F
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006213:Hallucinogens / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D047468:Immunoprecipitation / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
C501127:Dkk1 protein, mouse; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse; D038362:Glycogen Synthase Kinase 3; D018817:N-Methyl-3,4-methylenedioxyamphetamine