期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 71, 期 11, 页码 1009-1017出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3182729845
关键词
Alzheimer; Amyloid; Cerebral amyloid angiopathy; Cerebrovasculature; Gamma secretase; Gelsolin; Imaging; Multiphoton
资金
- National Institutes of Health [EB00768, AG021084, AG005134]
- Harvard NeuroDiscovery Center
- ISCIII Subdireccion General de Evaluacion y Fomento de la Investigacion [PS09/00969]
- Proyectos Excelencia Junta Adalucia [CTS-7847]
- Fundacion Dr. Eugenio Rodriguez Pascual
- [Ramon y Cajal-2008-02333]
Cerebral amyloid angiopathy (CAA), the accumulation of beta-amyloid (A beta) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of A beta deposition in and clearance from vascular walls and their relationship to the concentration of A beta in the brain are poorly understood. We manipulated A beta levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding peripheral sink'' protein gelsolin and direct inhibition of its formation via administration of LY-411575, a small-molecule gamma-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% +/- 0.15% and 0.52% +/- 0.09% to 0.11% +/- 0.18% (p = 0.04) and -0.17% +/- 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (-0.004% +/- 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble A beta but without evidence of substantial amyloid clearance from vessels.
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