Aims

In Alzheimer’s disease (AD) the enzyme acetylcholinesterase (AChE) co-localizes with phosphorylated tau (P-tau) within the neurofibrillary tangles. Previously we have demonstrated that AChE is increased in a mutant tau mouse model. Here we have studied whether modulation of glycogen synthase kinase-3β (GSK3β) phosphorylated tau influences AChE expression.

Methods

P-tau levels were increased in SH-SY5Y cells by over-expression of human wild- type tau and GSK3β, then AChE enzymatic activity, protein and transcript levels were measured

In aliquots of cerebrospinal fluid (CSF) from AD patients enrolled in a clinical trial of tideglusib, an irreversible GSK3β inhibitor AChE enzymatic activity, P-tau, tau and Aβ42 levels were analyzed.

Results

AChE enzymatic activity and protein levels were increased (20 ± 2 % and 440 ± 150 % respectively) in in overexpressing P-tau SH-SY5Y cells, corresponding this increase to the cholinergic ACHE-T variant. In addition, an imbalance in cholinergic activity with a decrease in cellular levels of the neurotransmitter acetylcholine (45 ± 10 %) was demonstrated in overexpressing P-tau SH-SY5Y cells differentiated to neurons. A direct interaction between P-tau and AChE was also demonstrated. Regarding CSF from Tideglusib clinical trial, AChE activity at the end of the treatment were higher (35 ± 16 %) in placebo-treated patients, probably as result of the treatment with AChE inhibitors. However this increment was not observed in tideglusib treated patients. Furthermore P-tau prior treatment correlated with AChE activity.

Conclusions

P-tau interacts with AChE and can modulate its expression suggesting a possible increment on AChE at initial phases of AD.