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<p>In Alzheimer’s disease (AD), hyperphosphorylated tau propagates across brain regions through its seeding activity, much like prions. We assessed regional tau seeding activity and phosphorylation by RT-QuIC, western blotting (WB), and mass spectrometry in entorhinal cortex (ENT), inferior/middle/superior temporal gyri (ITG/MTG/STG), and cerebellum (CER). Tau-seeding was highest in ENT among the brain regions examined and correlated positively with Braak staging. AD-derived RT-QuIC products formed tau fibrils, propagating intracellularly in cell models. WB showed significantly higher pTau217/pTau396 in ITG vs. STG/CER. Seeding-activity correlated with WB levels of pTau217/pTau262/pTau396 (<i>p</i> = 0.004, <i>p</i> = 0.0028, <i>p</i> = 0.003) and Braak/Thal staging in temporal regions. Anti-tau antibodies varied in immunodepleting seeding (pTau217 &gt; TAU5 &gt; pTau181 &gt; pTau396). Mass spectrometry identified 11 phospho-sites in ITG tau, while pTau231/pTau262/pTau263/pTau396 were AD-specific. Regional tau-seeding correlates with local phospho-tau levels and pathology, supporting plasma pTau217 for diagnosis and seeding activity as a potential biomarker.</p>

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Regional variations in seeding activity, phosphorylation, and protein levels of tau in Alzheimer’s disease brain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Yirong Yang,
  • Huiying Guan,
  • Zihao Zhang,
  • Hailun Wu,
  • Ying Xiong,
  • Can Xu,
  • Hengxu Mao,
  • Wuxin You,
  • Yaoyun Kuang,
  • Qilei Zhang,
  • Hancun Yi,
  • Mengting Li,
  • Yuejun Gu,
  • Chengsi Wu,
  • Kuan Ning,
  • Pengcheng Huang,
  • Xiao-Xin Yan,
  • Ansgar Poetsch,
  • Yang Shi,
  • Zhong Pei,
  • Ping-Yi Xu,
  • Yue Huang,
  • Daojun Hong,
  • Wen-Quan Zou

摘要

In Alzheimer’s disease (AD), hyperphosphorylated tau propagates across brain regions through its seeding activity, much like prions. We assessed regional tau seeding activity and phosphorylation by RT-QuIC, western blotting (WB), and mass spectrometry in entorhinal cortex (ENT), inferior/middle/superior temporal gyri (ITG/MTG/STG), and cerebellum (CER). Tau-seeding was highest in ENT among the brain regions examined and correlated positively with Braak staging. AD-derived RT-QuIC products formed tau fibrils, propagating intracellularly in cell models. WB showed significantly higher pTau217/pTau396 in ITG vs. STG/CER. Seeding-activity correlated with WB levels of pTau217/pTau262/pTau396 (p = 0.004, p = 0.0028, p = 0.003) and Braak/Thal staging in temporal regions. Anti-tau antibodies varied in immunodepleting seeding (pTau217 > TAU5 > pTau181 > pTau396). Mass spectrometry identified 11 phospho-sites in ITG tau, while pTau231/pTau262/pTau263/pTau396 were AD-specific. Regional tau-seeding correlates with local phospho-tau levels and pathology, supporting plasma pTau217 for diagnosis and seeding activity as a potential biomarker.