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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Intravital imaging of the superficial brain tissue in mice represents a powerful tool for the dissection of the cellular and molecular cues underlying inflammatory and infectious central nervous system (CNS) diseases. We present here a step-by-step protocol that will enable a non-specialist to set up a two-photon brain-imaging model. The protocol offers a two-part approach that is specifically optimized for imaging leukocytes but can be easily adapted to answer varied CNS-related biological questions. The protocol enables simultaneous visualization of fluorescently labeled immune cells, the pial microvasculature and extracellular structures such as collagen fibers at high spatial and temporal resolution. Intracranial structures are exposed through a cranial window, and physiologic conditions are maintained during extended imaging sessions via continuous superfusion of the brain surface with artificial cerebrospinal fluid (aCSF). Experiments typically require 1-2 h of preparation, which is followed by variable periods of immune cell tracking. Our methodology converges the experience of two laboratories over the past 10 years in diseased animal models such as cerebral ischemia, lupus, cerebral malaria, and toxoplasmosis. We exemplify the utility of this protocol by tracking leukocytes in transgenic mice in the pial vessels under steady-state conditions.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a protein conformational disorder characterized by two major neuropathological features: extracellular accumulations of amyloid-β peptides in the form of plaques and intracellular tangles, consisting of hyperphosphorylated tau proteins. Several morphological and functional changes are associated with these lesions in the diseased brain, such as dendritic and synaptic alterations, as well as microglial and astroglial recruitment and their activation. The availability of transgenic mouse models that mimic key aspects of the disease in conjunction with recent advances in two-photon imaging facilitate the study of fundamental aspects of AD pathogenesis and allow for longitudinally monitoring the efficacy of therapeutic interventions. Here, we review the ambitious efforts to understand the relationship between the main neuropathological hallmarks of AD and their associated structural and functional abnormalities by means of in vivo two-photon imaging.
Frontiers in Psychiatry 04/2012; 3:26. DOI:10.3389/fpsyt.2012.00026
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