Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy

Yingjian You, Abigail Perkins, Pablo Cisternas, Braulio Muñoz, Xavier Taylor, Yanwen You, Holly J. Garringer, Adrian L. Oblak, Brady K. Atwood, Ruben Vidal, Cristian A. Lasagna-Reeves

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined. We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau. Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Feb 26 2019

Keywords

  • ADan oligomers
  • Cerebral amyloid angiopathy
  • Neurodegeneration
  • Tau downregulation
  • Tau oligomers
  • Vascular amyloid

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    You, Y., Perkins, A., Cisternas, P., Muñoz, B., Taylor, X., You, Y., Garringer, H. J., Oblak, A. L., Atwood, B. K., Vidal, R., & Lasagna-Reeves, C. A. (2019). Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy. Acta Neuropathologica Communications, 7(1). https://doi.org/10.1186/s40478-019-0680-z