Countering tauopathy with heparan sulfate derivatives

This collaborative, translational research project is aimed at countering tauopathy, the accumulation and toxic effects of hyperphosphorylated tau protein that underlie neurodegeneration in Alzheimer's disease (AD). Supported by a five-year, $3 million NIH R01 grant through NINDS, the project partners MSU with a team at the University of Virginia to interrogate mechanisms of tau-mediated neurotoxicity and to test therapeutic strategies that could be repurposed for clinical use.

The research addresses a critical gap in AD science: the ability to produce and test a bioactive form of hyperphosphorylated tau (p-tau) that reliably induces neuronal damage and cognitive deficits in animal models. The Kuo Lab has developed a recombinant p-tau produced in E. coli that mimics pathological features observed in patients and has been shown to cause behavioral and cognitive impairments in animal systems, including mice and fruit flies. Using a new mouse model, the teams will test the hypothesis that oligomeric forms of hyperphosphorylated tau drive neurotoxicity and that these damaging effects can be mitigated by small-molecule interventions.

Two prescription drugs identified in the Kuo Lab's pilot screens apomorphine and raloxifene emerged as potent inhibitors of p-tau cytotoxicity in vitro. Apomorphine, already used clinically to treat Parkinson's disease motor fluctuations, demonstrated in vivo potential to reduce behavioral and histological deficits caused by p-tau in preliminary studies, pointing to a promising route for drug repurposing. The current project will expand these findings, characterizing the mechanisms by which p-tau oligomers harm neurons, defining how apomorphine and raloxifene counteract those processes, and evaluating cognitive and histopathological outcomes in rigorously designed animal experiments.

By focusing on hyperphosphorylated tau as a likely driver of neuronal death in AD, the work aims to shift the field beyond amyloid-centric approaches and provide a translational bridge from molecular discovery to therapeutic intervention. Importantly, the implications extend beyond Alzheimer's disease: because tau pathology is implicated in multiple neurodegenerative disorders including Pick's disease, progressive supranuclear palsy, frontotemporal lobar degeneration, and chronic traumatic encephalopathy therapies that neutralize p-tau toxicity could have broader clinical relevance. The project also recognizes the potential role of tau aggregates in peripheral conditions, such as Type II diabetes and sporadic inclusion body myositis.

The collaborative, multidisciplinary effort is designed to produce mechanistic insights, validate candidate therapeutics, and generate the research products necessary to propel clinical development. If successful, the work could provide a new paradigm for treating tau-mediated neurodegeneration and offer repurposed, clinically actionable drugs to slow or prevent the cognitive decline associated with tauopathies.