Tau clearance improves astrocytic function and brain glutamate-glutamine cycle

Tau hyperphosphorylation is a critical factor in neurodegenerative diseases, including dementia and Parkinsonism. Existing animal models of tauopathies express tau in neurons within the forebrain and do not often show tau accumulation in the brainstem and astrocytes. This study aims to understand the effects of differential regional expression of tau on neurotransmitter balance in the brain. To obtain an animal model that expresses tau in the brainstem, we bred hemizygous mice that express P301L tau (TauP301L) and detected hyper-phosphorylated tau (p-tau) predominantly in the hippocampus, cortex, brainstem and thalamus. We previously demonstrated that TauP301L mice [26] express tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of human tauopathies. We treated TauP301L mice with tyrosine kinase inhibitors (TKIs) to determine the effects of tau clearance on neurotransmitter balance and astrocytic function. ¹³C/¹H MRS reveals astrocytic dysfunction via reduced glial aspartate and impaired glutamate-glutamine cycle. An increase in glutamate and GABA and decrease in glutamine were observed in homozygous mice compared to hemizygous and control littermates. Daily treatment with TKIs, nilotinib or bosutinib led to p-tau clearance via autophagy and reversal of neurotransmitter imbalance. These data suggest that accumulation of p-tau in the brainstem does not alter dopamine metabolism but may trigger glutamate toxicity and astrocytic dysfunction in the TauP301L mouse. TKIs reverse tau effects via reversal of neurotransmitter imbalance.