Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice

Julia L. Gregory, Claudia M. Prada, Sara J. Fine, Monica Garcia-Alloza, Rebecca A. Betensky, Michal Arbel-Ornath, Steven M. Greenberg, Brian J. Bacskai, Matthew P. Frosch

Research output: Contribution to journalArticle

Abstract

Cerebral amyloid angiopathy (CAA), the accumulation of βamyloid (Aβ) 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 Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain are poorly understood. We manipulated AA 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 smallmolecule γ-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% T 0.18% (p = 0.04) and j0.17% ± 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 (j0.004% ± 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 Aβ but without evidence of substantial amyloid clearance from vessels.

Original languageEnglish (US)
Pages (from-to)1009-1017
Number of pages9
JournalJournal of Neuropathology and Experimental Neurology
Volume71
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • Alzheimer
  • Amyloid
  • Cerebral amyloid angiopathy
  • Cerebrovasculature
  • Gamma secretase
  • Gelsolin
  • Imaging
  • Multiphoton

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Gregory, J. L., Prada, C. M., Fine, S. J., Garcia-Alloza, M., Betensky, R. A., Arbel-Ornath, M., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (2012). Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice. Journal of Neuropathology and Experimental Neurology, 71(11), 1009-1017. https://doi.org/10.1097/NEN.0b013e3182729845