Late onset neurodegenerative diseases, such as Alzheimer?s disease (AD), affect more than 7 million Americans, with the associated healthcare costs currently reaching hundreds of billions of dollars per year (and constantly rising). It is known that the pathology of AD involves many more cell types than the neurons of the hippocampus and cortex. The cells that comprise the brain vasculature, including the endothelial cells, pericytes, astrocytes and smooth muscle cells are critically important in maintaining the balance of health and disease in the brain. In particular, many properties of the endothelial cells, including their roles in establishing the blood-brain barrier (BBB), delivering nutrients to the brain, and regulating the proliferation of neural stem cells, are essential to proper brain function. Studies from our lab and others have demonstrated that brain vasculature can be restored even after it has been damaged, suggesting new strategies for treating neurodegenerative disorders via improving the integrity of brain vasculature. In experiments detailed in this application, we propose to both identify and correct processes within the cells of the brain vasculature that are known to be affected in Alzheimer?s disease and other dementias. Some of our work is based on the acknowledgement that aging is the major risk factor for dementia and is also characterized by declining vasculature. As a step toward obtaining a comprehensive understanding of aging-associated changes in the brain, our lab recently published a large single-cell RNAseq study comparing young and old mouse brains. Here, we propose to exploit our knowledge of the gene expression changes that define the aging process to identify cellular and molecular factors critical to brain blood vessel function and the maintenance of the BBB in a mouse model of AD. First, we will test several different hypotheses concerning the cellular and molecular bases for the vascular defects in the AD brain. Surprisingly, recent literature suggests that some of these changes are mediated by soluble factors and may be reversible. To explore this possibility in greater detail, we will use our knowledge of the CNS network of cell-cell interactions mediated by secreted factors to identify potentially correctable changes that occur in AD vasculature. Finally, we will use our lab?s expertise in human induced pluripotent stem cells (iPSCs) to employ an in vitro model of the BBB. This in vitro platform will serve as an important complementary approach to the in vivo mechanistic evaluation of putative aging or rejuvenation factors in human brain vascular cells. At the same time, we propose modifications of the current in vitro system that should improve its ability to recapitulate properties of the in vivo BBB. Together, our proposed studies seek to identify and validate new modulators of brain vasculature and to elucidate how the functions of these modulators play a role in the maintenance or degradation of the BBB in dementia.
Declining brain vasculature is a key, but understudied, component of several age ? associated neurodegenerative disorders including Alzheimer?s disease (AD) and related dementias. The research described in this proposal uses a combination of bioinformatics, mouse studies and human pluripotent stem cell modeling to identify and characterize novel AD-related pathways and factors involved in the maintenance or deterioration of blood vessels and the blood-brain barrier. Identifying factors that slow or reverse the decline of brain vasculature could be a new therapeutic avenue for these devastating and deadly disorders.
