A new paradigm for the treatment of alzheimer's disease: Targeting vascular activation

Paula Grammas, Joseph Martinez, Alma Sanchez, Xiangling Yin, Jarred Riley, Dylan Gay, Katherine Desobry, Debjani Tripathy, Jinhua Luo, Marianne Evola, Alice Young

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

No disease-modifying therapies are currently available for Alzheimer's disease (AD), a neurodegenerative disorder that affects more than 36 million people worldwide. Although cardiovascular risk factors such as hypertension and diabetes are increasingly implicated as contributing to the development of AD, the mechanisms whereby these factors influence pathological processes in the AD brain have not been defined. Here we propose, for the first time, vascular activation as a relevant mechanism in AD pathogenesis. We explore this hypothesis in two transgenic AD animal models: AD2576APPSwe (AD2576) and LaFerla 3xTg (3xTgAD) mice using the vascular activation inhibitor sunitinib. Our data show that in both AD animal models, the cerebrovasculature is activated and overexpresses amyloid beta, thrombin, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and matrix metalloproteinase 9. Oral administration of sunitinib significantly reduces vascular expression of these proteins. Furthermore, sunitinib improves cognitive function, as assessed by several behavioral paradigms, in both AD animal models. Finally, oxidant injury of brain endothelial cells in culture, resulting in expression of inflammatory proteins, is mitigated by sunitinib. The current data, as well as published studies showing cerebrovascular activation in human AD, support further exploration of vascular-based mechanisms in AD pathogenesis. New thinking about AD pathogenesis and novel, effective treatments are urgently needed. Identification of 'vascular activation' as a heretofore unexplored target could stimulate translational investigations in this newly defined area, leading to innovative therapeutic approaches for the treatment of this devastating disease.

Original languageEnglish
Pages (from-to)619-630
Number of pages12
JournalJournal of Alzheimer's Disease
Volume40
Issue number3
DOIs
StatePublished - 2014

Keywords

  • Alzheimer's disease
  • angiogenesis
  • behavior
  • cognitive decline
  • sunitinib

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    Grammas, P., Martinez, J., Sanchez, A., Yin, X., Riley, J., Gay, D., Desobry, K., Tripathy, D., Luo, J., Evola, M., & Young, A. (2014). A new paradigm for the treatment of alzheimer's disease: Targeting vascular activation. Journal of Alzheimer's Disease, 40(3), 619-630. https://doi.org/10.3233/JAD-2014-132057