Project Description

Vascular disease is the second most common cause of intellectual loss in the elderly and accelerates neurodegeneration in Alzheimer’s disease.  We have developed a novel model of subcortical ischemic vascular disease (SIVD) in the spontaneously hypertensive stroke prone rat (SHR/SP) that has the major features of the human disease. It involves feeding 12-week old SHR/SP the Japanese Permissive Diet (JPD) and performing a unilateral carotid artery occlusion (UCAO); this produces progressive demyelination with expression of MMPs, caspase-mediated oligodendrocyte death, and behavioral changes and death by the 16th week.   Recently, we showed an increase in hypoxia inducible factor-1 (HIF-1) with the JPD and UCAO, increased myelin basic protein, matrix metalloproteinase-9 (MMP-9) expression, disruption of the blood-brain barrier (BBB), death of the mature oligodendrocytes, and impaired learning in the Morris water maze.  MRI studies in other rats showed white matter injury occurred around the 15th week, suggesting that the hypoxia was driving the damage to the white matter. We suggest the following mechanisms of white matter damage: 1) an initial tissue hypoxic hypoperfusion of the deep white matter secondary to the hypertensive damage to the blood vessels; 2) an induction of HIF-1 with expression of MMP-9, which disrupts the BBB, and ultimately death of the oligodendrocytes.