Researchers in Texas have proposed that vascular activation contributes to the pathogenesis of Alzheimer’s disease, resulting in the overexpression of amyloid-beta and other factors (Grammas et al. J Alzheimers Dis 2014;40:619-630).      

The group used two transgenic mouse models to investigate the effects of sunitinib (Sutent), a tyrosine kinase inhibitor currently approved for the treatment of gastrointestinal stromal tumours and renal cell carcinoma. Sunitinib has antiangiogenic effects through its interaction with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors.

In the AD animal models, the cerebral vasculature was activated, overexpressing amyloid-beta, thrombin, TNF-alpha, interleukin-1 beta and IL-6, and matrix metalloproteinase (MMP)-9. A separate study recently reported alterations in MMP levels in CSF in AD patients versus controls (Mroczko et al. J Alzheimers Dis 2014;40:351-357).

In the animal study, vascular activation was reduced with sunitinib. The result was improvements in cognition, as assessed by behavioural paradigms, and a reduction in the expression of inflammatory proteins associated with oxidant injury to brain endothelial cells in culture.

Additional studies are needed to explore potential vascular mechanisms associated with AD pathogenesis.

Comment
Dr. Yves Bacher:  This interesting study may be a valuable addition to the field of Alzheimer and mixed-dementia pathology. It is a very seductive idea to include ischemia, inflammatory and amyloid pathology.