Cerebral amyloid angiopathy (CAA), the age-related deposition of cerebrovascular ft-amyloid (AH), is a common cause of hemorrhagic stroke, an accompanying pathology in most cases of Alzheimer disease (AD), and a potential cause of adverse responses to anti-All immunotherapeutic approaches to AD. Studies of CAA in the postmortem human brain are limited by the inability to make observations over time as the disease progresses. We have used in vivo multiphoton microscopy in mouse models of CAA to define the spatial and temporal progression of the disease in living animals. We have shown that cerebrovascular AH deposition occurs predictably with readily measured kinetics and that passive immunotherapy alters the progression of CAA and can lead to clearance of amyloid deposits from vessel walls. The consequences of CAA are associated in part with breakdown of the vessel wall. For this reason, we now propose to use novel methods to define the mechanisms that underlie Ali-induced vascular wall injury, including oxidative stress, activation of matrix metalloproteinases and other proteases and injury to vascular smooth muscle cells.
In Specific Aim #1, we will perform serial imaging of CAA progression in mouse models and define the spatial and temporal relationship between amyloid deposition and markers of injury to the vessel wall. The goal of this aim will be a precise understanding of the sequence of events in the pathway that lead to vascular wall injury.
In Specific Aim #2, we will examine which of the CAA-induced alterations in vessel wall injury can be interrupted or reversed by clearance of Afi using passive immunization and other methods. Because mouse models are only relevant in as much as they speak to human disease, in Specific Aim #3, we will determine which of our validated set of markers of vascular wall injury from mouse models are also found in human CAA. We will make use of our expertise in the clinical and neuropathologic characteristics of CAA and our access to a wide range of human samples (including sporadic CAA, CAA linked to APP mutations, tissue from the AN1792 trial of the Aft vaccine and familial British and Danish dementias. From these studies we will develop a clearer understanding of (1) mechanisms by which AIS deposition results in vascular wall injury and neurologic injury;(2) points suitable for therapeutic intervention;and (3) risks associated with the CAA in patients undergoing anti-amyloid therapies for Alzheimer disease.
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