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The Journal of Neuroscience, January 11, 2006, 26(2):365-371; doi:10.1523/JNEUROSCI.3854-05.2006

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Neurobiology of Disease
Kinetics of Cerebral Amyloid Angiopathy Progression in a Transgenic Mouse Model of Alzheimer Disease

Elissa M. Robbins,^1,5 Rebecca A. Betensky,² Sarah B. Domnitz,^1,5 Susan M. Purcell,^1,5 Monica Garcia-Alloza,^1,5 Charles Greenberg,^1,5 G. William Rebeck,³ Bradley T. Hyman,^1,5 Steven M. Greenberg,^1,5 Matthew P. Frosch,^1,4,5 and Brian J. Bacskai^1,5

¹Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, ²Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, ³Department of Neuroscience, Georgetown University, Washington, DC 20057, ⁴C. S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, and ⁵Harvard Medical School, Boston, Massachusetts 02115

Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular -amyloid (A) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular -amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like A. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3–0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.

Key words: amyloid-; Alzheimer; vascular; angiopathy; mouse; transgenic

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Received June 15, 2005; accepted October 30, 2005.

This article has been cited by other articles:

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