Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease. J Neurosci Off J Soc Neurosci

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2006; 26(2):365-71. DOI: 10.1523/JNEUROSCI.3854-05.2006
Source: PubMed


Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) 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 beta-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 Abeta. 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.

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    • "The white matter lesions generally correspond to hyperintensities observed on MRI, which, however, can also reflect other pathological substrates (Gouw et al., 2011). The white matter lesions evolve over time by expansion of existing lesions, rather than formation of new foci (Maillard et al., 2012), resembling the patterns of progression of amyloid angiopathy (Alonzo et al., 1998; Robbins et al., 2006). The expansion of the white matter lesions correlates with the evolution of the cognitive impairment (Maillard et al., 2012), new lacunes causing a steeper decline, especially in motor speed and executive functions (Jokinen et al., 2011). "
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    • "The frame is designed to fit within the small area typically available between the nose of the dipping objective and the stage of the microscope. Although the technique is optimized for leukocyte imaging, 2P-IBI can find varied applicability including for the study of the microenvironment of solid tumors (Yuan et al., 1994), microglial function (Davalos et al., 2005), and amyloid plaque deposition in Alzheimer disease (Robbins et al., 2006). 2P-IBI does not require extensive surgical preparation for absolute sterility as it is performed on anesthetized non-recovery animals. "
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    Frontiers in Cellular Neuroscience 01/2013; 6:67. DOI:10.3389/fncel.2012.00067 · 4.29 Impact Factor
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    • "Thus in vivo imaging of APP transgenic mice at weekly intervals, starting at the age of 8–11 months, showed that the emergence of CAA is a multifocal event in form of band-like Aβ deposits (Robbins et al., 2006). Furthermore, in contrast to the accumulation of amyloid plaques in the parenchyma, CAA progression tends to propagate from already existing deposits (Robbins et al., 2006). Therapeutic interventions, such as passive immunization, was able to halt CAA progression and even to reduce vascular amyloid in APP transgenic mice, as demonstrated by immunohistochemical analysis (Schroeter et al., 2008; Cattepoel et al., 2011). "
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