Intracerebroventricular phospho-tau immunotherapy alleviates cortical phospho-tau burden and motor phenotype in a neuron-specific P301S tauopathy mouse

Abstract

Pathological tau accumulation disrupts neuronal function, leading to neurodegeneration and dementia in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Despite the progression of several anti-tau therapies to clinical trials, no disease-modifying treatments for tauopathies exist. Tau hyperphosphorylation is a key factor in pathology progression. Among all tau phosphorylation sites targeted in preclinical passive immunization studies, the classic AT8 pathological tau phosphorylation sites have remained understudied. Thus, we investigated the potential of immunotherapy against phosphorylated tau (pTau) in a P301S mouse model of tauopathy. We administered a new monoclonal B6 antibody that targets tau phosphorylation sites at serine 202, threonine 205 and serine 208 either systemically for 3 months or locally into the cerebral ventricles for 1 or 2 months via an osmotic minipump. Systemic administration failed to reach the brain effectively, and subsequently, was not able to alleviate the progressive motor impairment seen in this tauopathy mouse model. By contrast, intraventricular administration improved motor function in earlier stages of pathology but had a lesser effect in later stages. The local administration for 8 weeks reduced the number of pTau positive neurons in cortex and hippocampus. Our findings indicate that targeting the classical pathological tau phosphorylation sites can ameliorate tau pathology and improve function in a mouse tauopathy model. These results add to growing evidence supporting the efforts in developing tau-targeting immunotherapies for neurodegenerative diseases associated with pathological tau deposits.