title: A new paradigm for the treatment of Alzheimer's disease: targeting vascular activation.
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.
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Paula
authors: P
authors: Grammas
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Joseph
authors: J
authors: Martinez
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Alma
authors: A
authors: Sanchez
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Xiangling
authors: X
authors: Yin
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Jarred
authors: J
authors: Riley
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Dylan
authors: D
authors: Gay
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Katherine
authors: K
authors: Desobry
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Debjani
authors: D
authors: Tripathy
authors: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Jinhua
authors: J
authors: Luo
authors: Texas Tech University Office of the Vice President for Research, Lubbock, TX, USA.
authors: Marianne
authors: M
authors: Evola
authors: Texas Tech University Office of the Vice President for Research, Lubbock, TX, USA.
authors: Alice
authors: A
authors: Young
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D000077210:Sunitinib; D013997:Time Factors; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D020533:Angiogenesis Inhibitors; D000933:Antifibrinolytic Agents; D007211:Indoles; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011758:Pyrroles; D024483:Vitamin K 3; D000077210:Sunitinib
keywords: Alzheimer's disease; angiogenesis; behavior; cognitive decline; sunitinib