Senescence induced by iron overload in the brain vasculature

University Of Texas Hlth Sci Ctr Houston, Houston TX

Investigators

Abstract

Iron is the most abundant metal in the brain, and its metabolism regulation is critical for brain function. Disturbance of the correct balance of iron levels in the brain, either its deficiency or its excess, causes multiple types of brain disorders. The effects of iron overload in the brain are less studied than those caused by iron deficiency. Indeed, iron overload causes cognitive dysfunction and occurs in many types of dementia, including Alzheimer's disease and vascular dementia. We use an iron overload model in aged mice in which female mice are more dramatically affected by iron overload than male mice. We observed that the brain vasculature of aged female mice treated with iron overload showed enhanced senescence-associated phenotype. We observed that the gene that codes for the endothelial-specific transmembrane protein Robo4, which participates in cell proliferation and senescence inhibition, was downregulated in the brain endothelium of aged females, compared with aged males. We demonstrated that Robo4 downregulation exacerbated iron-induced senescence in cultured primary cerebral endothelial cells. Senescence in the brain endothelium leads to impairment of vascular integrity, enhanced permeability, and accumulation of toxic substances in the brain parenchyma, which negatively affects cognitive functions. It has been demonstrated that iron accumulation in the brain, which occurs with aging, is the cause of the pathology of brain disorders such as Alzheimer's Disease, and not a consequence. However, the mechanisms by which iron accumulates in the brain are not known. We hypothesize that the sex chromosome complement contributes to higher vulnerability to iron overload in female mice vs male mice with aging, and that specifically overexpressing Robo4 in the brain vasculature of aged female mice can prevent endothelial senescence, brain iron deposition, and cognitive dysfunction induced by iron overload. To test our hypothesis, we propose two independent aims: In Aim 1, we will use a mouse model called Four Core Genotypes to identify the role of the sex chromosome complement on the sex-dependent vulnerability to iron overload in the brain of young and aged mice. In Aim 2, we will specifically target the brain vasculature of aged mice to determine if Robo4 overexpression prevents endothelial senescence, brain iron accumulation, and cognitive dysfunction induced by iron overload. This study will identify the role of the sex chromosome complement and Robo4 as factors that contribute to endothelial senescence, brain iron accumulation, and cognitive impairment in brain disorders associated with iron overload. In addition, this study highlights the importance of targeting the brain vasculature to mitigate the deleterious effects of iron overload and identifying potential sex differences in these disorders.