Neuroprotection of cholinergic neurons with tau aggregation inhibitor and rivastigmine in L1 mice with Alzheimer’s‐like tauopathy

Abstract Background Basal forebrain cholinergic dysfunction, likely linked to tau aggregation pathology, is a characteristic feature of AD. Cholinergic neurons contain choline acetyltransferase (ChAT) and high‐affinity tropomyosin‐related kinase A (TrkA) and send efferents to cortex and hippocampus where they release acetylcholine (ACh). The vesicular acetylcholine transporter (VAChT) is responsible for loading ACh into secretory vesicles and acetylcholine esterase (AChE) hydrolyses ACh in the synaptic cleft. We here aimed to evaluate the cholinergic phenotype in the Line 1 animal model of tauopathy and to determine the effect of the choline esterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor hydromethylthionine on the cholinergic system. Method Line 1 (L1) and control NMRI mice, 8‐9 months old, divided into 13 groups (n = 5 each), were treated with rivastigmine (0.1 and 0.5 mg/kg) and hydromethylthionine (5 and 15 mg/kg) and their combinations for 11 weeks. Immunohistochemical staining in brain sections was performed for ChAT, TrkA, VAChT and tau with a repeat domain monoclonal antibody (TauRx Therapeutics Ltd.). AChE activity was measured histochemically. The state of the cholinergic system was determined by stereological counting of ChAT‐ir and TrkA‐ir neurons, while Relative Optical Intensity (ROI) was used to tau immunoreactivity in basal forebrain, and cholinergic projections were evaluated using VAChT and AChE ROI. Result Number of ChAT‐ir, TrkA‐ir neurons and ROI value for VAChT and AChE were significantly lower while ROI value for tau was higher in vehicle‐treated L1 mice compared with wild type control. Numbers of ChAT‐ir, TrkA‐ir neurons and ROI value of VAChT and AChE in L1 mice were increased and tau ROI was decreased by hydromethylthionine treatment. Combined treatment decreased numbers of ChAT‐ir, TrkA‐ir neurons and ROI for VAChT and AChE compared to L1 groups treated with hydromethylthionine alone. Conclusion There was a significant loss of cholinergic basal forebrain neurones, impaired cholinergic projection and increased tau staining in L1 mice. Monotherapy with hydromethylthionine improved the cholinergic neurons phenotype, enhanced their projection and reduced tau pathology. Combination therapy interacted negatively attenuating the effect of hydromethylthionine given alone.