title: Rapid cell death is preceded by amyloid plaque-mediated oxidative stress.
abstract: Neuronal loss is the ultimate outcome in a variety of neurodegenerative diseases and central nerve system disorders. Understanding the sequelae of events that leads to cell death would provide insight into neuroprotective approaches. We imaged neurons in the living brain of a mouse model of Alzheimer's disease that overexpresses mutant human amyloid precursor protein and presenilin 1 and followed the death of individual neurons in real time. This mouse model exhibited limited neurodegeneration and atrophy, but we were able to identify a small fraction of vulnerable cells that would not have been detectable by using standard approaches. By exploiting a genetically encoded reporter of oxidative stress, we identified susceptible neurons by their increased redox potential. The oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h. Thus, local oxidative stress surrounding plaques contributes to long-range toxicity and selective neuronal death in Alzheimer's disease.
authors.affiliation: MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.forename: Steven
authors.initials: S
authors.lastname: Hou
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.forename: Maria
authors.initials: M
authors.lastname: Sekutowicz
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kelly
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001284:Atrophy; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000378:metabolism*; D013997:Time Factors
chemical_list: D049452:Green Fluorescent Proteins; D020169:Caspases
keywords: in vivo imaging; reduction-oxidation sensitive GFP