Study of cerebrovascular dysfunction in Alzheimer's disease: possible involvement of IL-33 and oxidative stress

Abstract

In Alzheimer's disease (AD) two major proteins, the beta-amyloid protein (A²) and the tau protein, are accumulated in the brain. This leads to the loss of connections between nerve cells and eventually to the death of these cells, triggering dementia. The pathophysiological mechanisms responsible for triggering AD are uncertain. One of the hypotheses is that the cerebral amyloid accumulation occurs due to an impairment in A² clearance. Changes in cerebrovascular function represent a potential mechanism of decreased clearance of A². Interleukin-33 (IL-33), an IL-1 cytokine, which acts to increase endothelial permeability, has decreased transcription levels in patients with AD. Thus, it is possible that IL-33 plays an important role in A² clearance in AD. In addition, studies suggest that risk factors for the development of cardiovascular disease may trigger AD. In fact, pathologies such as obesity, diabetes, and atherosclerosis promote increased production of reactive oxygen species. Oxidative stress is related to the development of AD and the lower expression of IL-33, which may be responsible for the decrease of this cytokine in AD. In this sense, the aim of the present project is to evaluate if mechanisms involved in the cerebrovascular control or, more specifically, if IL-33 levels and oxidative stress decrease are involved in A² clearance in AD. To do so, we will test the hypothesis that oxidative stress decreases IL-33 expression, decreasing vascular permeability and, consequently, A² clearance, potentiating amyloid plaque formation and vascular disease-related dysfunction. To test this hypothesis we will use transgenic mice for AD, mice that do not express the receptor for IL-33, ST2 receptor, and db/db diabetic mice. We will perform trials to evaluate cerebrovascular and cognitive characteristics and to assess how IL-33 levels interfere with soluble A² expression and amyloid plaque deposition.