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.