Rivastigmine interferes with the pharmacological activity of hydromethylthionine on presynaptic proteins in the line 66 model of frontotemporal dementia

The negative interference of treatments between the acetylcholinesterase inhibitor rivastigmine and the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) has been reported in Line 1 tau-transgenic mice, which overexpress a truncated species of tau protein that is found in the core of paired helical filaments in Alzheimer´s disease (AD). However, little is known about whether such interactions could affect synapses in mice overexpressing tau carrying pathogenic mutations. Here, we have used Line 66 (L66) mice which overexpress full-length human tau carrying the P301S mutation as a model in which tau accumulates in synapses. We measured the abundance of tau and synaptic proteins (VAMP-2, SNAP-25, SNTX-1, SYNPY-1, SYN-1, A-SYN) immunohistochemically to reveal structural synaptic alterations in these mice. Tau and synaptic markers were also examined in L66 mice treated with hydromethylthionine mesylate (HMTM) (15 mg/kg) and rivastigmine (0.5 mg/kg) administered singly and in combination. Tau protein accumulated in L66 mouse brains, and the levels of synaptic proteins were also altered, most notably with decreased levels of SNAP-25 and SYN-1. A decrease in tau accumulation in L66 brains caused by HMTM was partially compromised by rivastigmine pretreatment. Differences in synaptic proteins induced by HMTM alone were not identical with those induced by HMTM pretreated with rivastigmine. The most prominent differences appeared in proteins of the SNARE complex (SNAP-25, VAMP-2, SNTX-1), but rivastigmine also interfered with the HMTM-dependent reduction in tau accumulation. These data extend our previous findings with L1 mice and provide evidence for a synaptic mechanism of interference between symptomatic and disease-modifying dementia therapies and an explanation for similar drug interactions observed in clinical trials.