(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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015871-02
Application #
6169110
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, D Stephen
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$254,594
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158
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Wyss-Coray, Tony; Yan, Fengrong; Lin, Amy Hsiu-Ti et al. (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A 99:10837-42
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Wyss-Coray, T; Lin, C; Yan, F et al. (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612-8
Masliah, E; Ho, G; Wyss-Coray, T (2001) Functional role of TGF beta in Alzheimer's disease microvascular injury: lessons from transgenic mice. Neurochem Int 39:393-400
Wyss-Coray, T; Lin, C; Sanan, D A et al. (2000) Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am J Pathol 156:139-50