Abnormal aggregation of tau is the pathological hallmark of
tauopathies including
frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with
hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and
hydromethylthionine treatments of line 66 mice were compared. The brain
proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify
protein networks and pathways that were altered due to tau overexpression or modified by
hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/
mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by
hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and
protein ubiquitination were activated by
hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that
hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.