title: Targeting thrombin: an inflammatory neurotoxin in Alzheimer's disease.
abstract: The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets.
authors: Texas Alzheimer's Research and Care Consortium, Austin, TX, USA Garrison Institute on Aging, Texas Tech 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 Health Sciences Center, Lubbock, TX, USA.
authors: Joseph M
authors: JM
authors: Martinez
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000628:therapy*; D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D013917:Thrombin / Q000378:metabolism*
chemical_list: D000991:Antithrombins; D013917:Thrombin
keywords: Alzheimer's disease; cardiovascular risk factors; cerebral microvasculature; cognitive decline; dabigatran; thrombin; thrombin inhibitors