Therapeutic Treatment With OLX‐07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy

• DOI: 10.1111/jnc.70025
• Publication Date: 2025-03-12T04:29:50Z
• Authors: E. J. Davidowitz; P. Lopez; D. Patel; H. Jimenez; A. Wolin; J. Eun; L. Adrien; J. Koppel; D. Morgan; P. Davies; J. G. Moe

ABSTRACTTargeting tau protein is a strategy for the development of disease‐modifying therapeutics for Alzheimer's disease (AD) and numerous rare tauopathies. A small molecule approach targeting tau aggregation was used to select and optimize compounds inhibiting tau self‐association in vitro that have translated in vivo in preventive studies in htau and P301L tau JNPL3 mouse models of tauopathy. In this therapeutic treatment study, aged JNPL3 mice with pre‐existing tau aggregates were used to evaluate the therapeutic effect of OLX‐07010. The study had a Baseline group of mice aged 7 months, a vehicle, and two dose groups treated until 12 months by administration in feed. The primary endpoint of the study was the reduction of insoluble tau aggregates with statistical significance. The secondary endpoints were dose‐dependent reduction of insoluble tau aggregates, reduction of soluble tau, and improvement of motor behavior. ELISAs and immunoblots were used to determine the levels of tau and its aggregated forms including self‐associated tau and Sarkosyl insoluble tau. Effect on motor behavior, as measured by Rotarod assay, was also assessed between the treatment groups. At the end of treatment, reduced levels of self‐associated tau, Sarkosyl insoluble tau aggregates, and overall levels of tau in the heat‐stable fraction with statistical significance in the cortex were observed. Treatment prevented the accumulation of tau aggregates above baseline, and in parallel, treatment groups had improved motor behavior in a Rotarod assay compared to baseline and vehicle control groups, suggesting that treatment was rescuing motor impairment in aged mice. The functional and biochemical readouts suggest that this small molecule has potential for treating neurodegenerative diseases characterized by tau aggregation such as AD and progressive supranuclear palsy.image