(From Abstract): Cerebrovascular deposition of amyloid, or cerebral amyloid angiopathy (CAA), is a prime cause of normotensive intracerebral hemorrhages in the elderly. CAA is also a major neuropathological lesion in Alzheimer's disease (AD) and is accompanied by degenerating cells of the vascular wall. Because cerebrovascular amyloidosis has implications for the pathogenesis of Alzheimer's disease and for central nervous system (CNS) function in general, understanding its etiology is of great importance. Although it is known that single amino acid substitutions in several different proteins can cause rare autosomal dominant forms of CAA and that the apolipoprotein (apo) E e4 allele is a genetic risk factor for CAA, the cause of this disease in the majority of cases remains elusive. Through studies addressing the role of injury in neurodegenterative diseases, we have identified transforming growth factor (TGF)-ß1 as an inducer of cerebrovascular amyloidosis and as a potential pathogenic factor for CAA in human Alzheimer's disease cases. The cytokine TGF-ß1 is rapidly produced after all forms of CNS injury and may function as an organizer of the responses to brain injury. Overexpression of TGF-ß1 in astrocytes of transgenic mice caused cerebrovasular amyloid deposition and prominent perivascular astrocyte activation along with a degeneration of cortical capillaries reminiscent of Alzheimer's disease. Here we propose experiments to define the role of TGF-ß1 in cerebrovascular amyloidosis at the molecular level. We will determine whether chronic activation of astrocytes by TGF-ß1 is necessary and sufficient to cause cerebrovascular amyloidosis in vivo and whether this process is modulated by different human apoe isoforms. We will use transgenic mice that overexpress dominant-active or dominant-negative TGF-ß receptors in astrocytes or comparable levels of apoE3 or apoE4 in neurons. In addition, we will initiate studies to determine if chronic TGF-ß1 production and astrocytosis cause the capillary degeneration that precedes amyloid deposition and whether these processes can be modulated by apoE3 or apoE4. The proposed studies will allow us to better understand the etiology and pathogenesis of cerebrovascular amyloidosis in vivo and clarify the roles of TGF-ß1, CNS injury, and astrocyte activation in this process. Our findings will have implications for the pathogenesis of human CAA and Alzheimer's disease in general and will help to assess whether TGF-ß1 could be a future target of therapeutic interventions.
