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.

Brain venous haemodynamics, neurological diseases and mathematical modelling. A review

“…In the autoimmune theory the immune system for an unknown reason attacks self cells, following some triggering mechanisms that may be of genetic, environmental or infectious type. In this manner, as observed by some researchers [58], most current research on neurodegenerative diseases is highly neuron centred. The question being asked is: why does the immune system attack the myelin?…”

“…Perhaps the most prominent example is AD, with estimated 36 million patients worldwide and for which cardiovascular risks factors play a significant role [57,58]. The main purpose of this section is to identify a commonality, namely venous haemodynamics, occurring across a wide range of pathologies, noting that such commonality is being established largely as the result of the proposed CCSVI theory for MS.…”

“…It would therefore seem reasonable to take a step back and conduct research into the blood vessel wall, as a necessary step to begin to understand the phenomena. In the context of Alzheimer's disease (AD) and its so-called cardiovascular risk factors, Grammas and collaborators [57,58] advocate the development of pharmaceuticals specifically targeted to the vessel wall. An even bolder proposition would be to take another, further step back and investigate the complex mechanical forces present in the interaction of the flowing blood stream, whose components contain T cells, and the vessel wall subject to transient mechanical forces.…”

Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

“…Currently, it is in use for gastrointestinal stromal tumours, renal cell cancer and pancreatic cancer. Sunitinib was shown to decrease the amyloid burden and reverse cognitive decline in AD model mice, suggesting that if we target angiogenesis, we can revert the increase in the accumulation of Aβ and abate the cognitive decline associated with AD [76].…”

“…Anti-angiogenics, including small molecule tyrosine kinase inhibitors have been tested and approved as anti-cancer therapeutics and have shown to maintain normal vascular [75][76][77]. Sunitinib is a broad spectrum tyrosine kinase inhibitor.…”