APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis

Nigral tau hyperphosphorylation has been implicated as an initiation of nigrostriatal dopaminergic neurodegeneration. Apolipoprotein epsilon 4 allele (APOE4) is a common risk factor of Parkinson's disease (PD) and atherosclerosis (AS). Whether APOE4 carriers exhibited higher levels of nigral phosphorylated tau (p-tau) and the correlation between AS- and PD-related tauopathy remain elusive. Here, the tau pathology was observed in APOE4 carried and non-APOE4 carried AS patients postmortem brain substantia nigra pars compacta (SNpc). APOE3/3 and APOE4/4 knock-in mice treated with high fat diet (APOE3-HFD and APOE4-HFD, respectively) were used to simulate AS model. The tau-related neuropathology and behavioral performances were analyzed. Postmortem brain analysis showed that APOE4-carried AS patients exhibited elevated nigral p-tau level relative to non-APOE4 carriers. APOE4 mice fed with HFD exhibited higher p-tau, cholesterol accumulation, and larger AS plaque area in contrast to APOE3-HFD. Cholesterol triggered GSK3β activation, leading to tau phosphorylation in primary cultured neurons. Aiding cholesterol transport alleviated nigral cholesterol accumulation and tau pathology, thereby mitigating the tau-mediated nigrostriatal degeneration. This alleviated degeneration might also contribute to motor function recovery. These findings showed a link between nigral dopaminergic tau-related pathology and AS phenotype, and targeting cholesterol might alleviate both PD-like tauopathy and AS.