cis P-tau Accumulation Triggers Neurodegeneration after Ischemic Stroke

Ischemic stroke is a neurological deficit caused by a lack of blood supply to the brain. Evidence indicates that ischemic stroke leads to dementia of the Alzheimer’s disease (AD) phenotype; however, the underlying molecular mechanism remains unclear. Tau hyperphosphorylation is a common pathological feature of both ischemic stroke and AD. In human AD, the pThr231 residue preceding a pro residue is the primary phosphorylation site that emerges in the phosphorylation cascade before tau tangles, and its levels in cerebrospinal fluid can track AD progression. The pThr231-Pro motif in phosphorylated tau has two distinct cis or trans conformations. Unlike trans P-tau, cis P-tau is the neurotoxic tau conformer, acting as an early precursor of tau pathology in several neurodegenerative disorders, including AD. In a similar pattern, ischemic stroke triggers tau hyperphosphorylation, leading to the formation of tau tangles and promoting neuronal apoptosis. However, it is still unknown whether ischemic stroke induces pathogenic cis P-tau. In this study, we employed both in vitro and in vivo stroke models to investigate cis P-tau formation at different time points by performing immunoblotting and immunofluorescence analyses. We found that cellular stress due to a lack of oxygen and nutrients stimulates cis P-tau formation and accumulation, leading to cistauosis and ultimately neuronal cell death. Therefore, our results suggest a novel molecular mechanism for ischemic stroke and a therapeutic target to fight tau-mediated neurodegeneration after ischemic stroke.