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<p>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.</p>

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APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Shanshan Hu,
  • Xiaojia Peng,
  • Bing Xia,
  • Cihang Gu,
  • Baofei Sun,
  • Min Chang,
  • Jiuyang Ding,
  • Longying Peng

摘要

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.