PROJECT DESCRIPTION
This project addresses patients' recovery from stroke and the development of post-stroke dementia, a sub-
category of vascular dementia that affects approximately one-third of stroke sufferers. Following stroke, the
blood brain barrier (BBB) is breached in the area of the lesion. As part of a cellular repair response, reactive
astrocytes join together via an unknown mechanism to form a physical barrier to seal off the damaged area
and protect the surviving neuropil. Astrogliosis and the formation of the glial scar is a critical component of the
healing response to stroke. However, there have been no studies on the possibility that failure of the glial scar
to perfectly seal the area of injury, which we recently demonstrated is also a site of chronic inflammatory
responses, contributes to cognitive decline in patients that develop post-stroke dementia. This limitation has
been due, in part, to the lack of an effective animal model of delayed cognitive dysfunction following stroke.
However, we recently developed an innovative new mouse model of delayed cognitive dysfunction following
stroke that models hallmarks of post-stroke dementia. Using this model, we now have substantial evidence that
failure of the glial scar to segregate chronically leaky blood vessels within the lesion, as well as chronic
inflammatory responses occurring in the lesion, is one cause of post-stroke dementia. Therefore the goals of
this project are to determine for the first time precisely how (and how effectively) the glial scar seals the area of
injury following stroke, by identifying the cellular and molecular mechanisms involved, and then to manipulate
these mechanisms to enhance repair by the glial scar. These goals will be achieved by using our new mouse
model of delayed cognitive dysfunction following stroke in conjunction with confocal and electron microscopy,
immunohistochemistry, biochemical assays, flow cytometry, multiplex immunoassays, and behavioral studies,
in adult and aged wildtype and transgenic mice. At the end of these studies we will have revealed how well the
glial scar seals lesions following stroke in both adult and aged mice, interrogated a key pathway involved in
glial scar regulation for which there is little data, and pharmacologically manipulated this pathway to improve
the barrier function of the glial scar, and thereby protect against the development of post-stroke dementia.
