Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease

Chia Chen Liu, Yu Yamazaki, Michael G. Heckman, Yuka A. Martens, Lin Jia, Akari Yamazaki, Nancy N. Diehl, Jing Zhao, Na Zhao, Michael DeTure, Mary D. Davis, Lindsey M. Felton, Wenhui Qiao, Yonghe Li, Hongmei Li, Yuan Fu, Na Wang, Melissa Wren, Tomonori Aikawa, Marie Louise HolmHiroshi Oue, Cynthia Linares, Mariet Allen, Minerva M. Carrasquillo, Melissa E. Murray, Ronald C. Petersen, Nilüfer Ertekin-Taner, Dennis W. Dickson, Takahisa Kanekiyo, Guojun Bu

Research output: Contribution to journalArticle

Abstract

Introduction: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases. Methods: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aβ40], Aβ42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA. Results: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels. Discussion: Refining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2020

Keywords

  • Alzheimer's disease
  • blood-brain barrier
  • cerebral amyloid angiopathy
  • tau
  • tight junction

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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  • Cite this

    Liu, C. C., Yamazaki, Y., Heckman, M. G., Martens, Y. A., Jia, L., Yamazaki, A., Diehl, N. N., Zhao, J., Zhao, N., DeTure, M., Davis, M. D., Felton, L. M., Qiao, W., Li, Y., Li, H., Fu, Y., Wang, N., Wren, M., Aikawa, T., ... Bu, G. (Accepted/In press). Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease. Alzheimer's and Dementia. https://doi.org/10.1002/alz.12104