title: Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.
abstract: The pathogenic role of amyloid plaques in Alzheimer's disease (AD) remains controversial given poor correlation between plaque burden and cognitive status in clinicopathological studies. However, these postmortem studies cannot provide information about the dynamics of plaque expansion and consequent neurotoxicity. We developed a novel method for plaque birth-dating and growth analysis using sequential labeling with amyloid-binding dyes and postmortem quantitative confocal imaging. Using this technique in an AD mouse model, we find that plaques grow gradually over months with growth slowing in older animals. The degree of neuritic dystrophy correlates with the speed and extent of plaque enlargement suggesting a causal relationship. Surprisingly, new plaques induce a disproportionately large area of neuritic dystrophy whereas with older plaques the degree of injury plateaus despite continued growth. Our results suggest that the kinetics of amyloid deposition is a critical determinant of neurotoxicity, which is completely overlooked by traditional measures of plaque burden.
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, 420 East Superior St., Chicago, IL 60611, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Condello
authors.forename: Aaron
authors.initials: A
authors.lastname: Schain
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
mesh_terms: D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003287:Contrast Media; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods*; D058225:Plaque, Amyloid / Q000378:metabolism*; D013194:Staining and Labeling / Q000379:methods; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D005456:Fluorescent Dyes