APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis.
APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Zunyi, CN · Author affiliation
Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China. hsjixu@163.com.Location evidence
Guangzhou, CN · Author affiliation
Department of Neurology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, China.Location evidence
Guiyang, CN · Author affiliation
School of Forensic Medicine, Guizhou Medical University, Guiyang, 550025, China.Location evidence
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Original abstract
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.