Reduction in tau‐pathology induced with two novel tau aggregation inhibitors in Alzheimer mice

Background Alzheimer’s Disease (AD) is a common neurodegenerative disorder for which tau pathology is implicated. Abnormal forms of tau, which trigger neuronal dysfunction, can offer a therapeutic target. The main purpose of this study was to determine the effect of two new tau aggregation inhibitors here termed A and B, synthesised by TauRx Therapeutics Ltd., on tau pathology in a transgenic mouse model of AD. Method The research was conducted using the Line 1 (L1) transgenic mouse model with mild Alzheimer’s disease‐like tauopathy and the control wild‐type NMRI mice. L1 mice express a fragment of 945 amino acids fragment (296‐390) of the longest human tau CNS isoform (2N4R; htau40). Experiments were carried out on 20‐25 weeks old animals. Compounds A and B were administered orally at daily dose 1.5 and 7.5 mg/kg for six weeks. Level of tau pathology was examined immunohistochemically using mAb7/51. Images of stained brain sections were collected and analysed using ImageJ software. Tau staining was assessed using the relative optical intensity (ROI) in three areas of interest (AoI): dorsal CA1 and CA3 subfields of hippocampus and primary motor cortex. Three measures were applied: (i) overall mean ROI of all pixels within AoI; (ii) specific mean ROI calculated only for pixels within AoI, whose ROI was below a threshold, which was set manually, and (iii) %Area – ratio of number of all pixels in AoI with ROI below manually set threshold relative to the number of all pixels in AoI. Result Tau labelling was significantly enhanced in overall and specific mean ROI between NMRI and L1 mice (both untreated and treated) in all structures scrutinised. Drug efficacy was strongest in cortex where a clear reduction of tau immunolabelling was revealed, followed by CA3 subfield of the hippocampus. No efficacy was obtained for CA1 independent of analysis method. The analysis of % Area affected by tau was particularly sensitive for drug efficacy in both CA3 and cortex, but there was yet again no effect in CA1. Conclusion Two new tau aggregation inhibitors A and B both reduced the level of pathological tau deposits in L1 mice.