title: Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice.
abstract: Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (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 Aβ 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 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% ± 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 Aβ but without evidence of substantial amyloid clearance from vessels.
authors.affiliation: Department of Neurology/Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Gregory
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Prada
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Fine
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Michal
authors.initials: M
authors.lastname: Arbel-Ornath
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides