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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (03))
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
van Veluw, Susanne J; Kuijf, Hugo J; Charidimou, Andreas et al. (2017) Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy. Acta Neuropathol 133:409-415
Gurol, M Edip; Greenberg, Steven M (2013) A physiologic biomarker for cerebral amyloid angiopathy. Neurology 81:1650-1
Gregory, Julia L; Prada, Claudia M; Fine, Sara J et al. (2012) Reducing available soluble ?-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice. J Neuropathol Exp Neurol 71:1009-17
Klooster, Rinse; Rutgers, Kim S; van der Maarel, Silvère M (2012) Selection of VHH antibody fragments that recognize different A? depositions using complex immune libraries. Methods Mol Biol 911:241-53
Lee, Jeong Hyun; Bacskai, Brian J; Ayata, Cenk (2012) Genetic animal models of cerebral vasculopathies. Prog Mol Biol Transl Sci 105:25-55
Rutgers, Kim S; van Remoortere, Alexandra; van Buchem, Mark A et al. (2011) Differential recognition of vascular and parenchymal beta amyloid deposition. Neurobiol Aging 32:1774-83
Garcia-Alloza, Monica; Gregory, Julia; Kuchibhotla, Kishore V et al. (2011) Cerebrovascular lesions induce transient ?-amyloid deposition. Brain 134:3697-707
Linn, J; Halpin, A; Demaerel, P et al. (2010) Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 74:1346-50
Garcia-Alloza, Monica; Prada, Claudia; Lattarulo, Carli et al. (2009) Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J Neurochem 109:1636-47
Smith, Eric E; Greenberg, Steven M (2009) Beta-amyloid, blood vessels, and brain function. Stroke 40:2601-6

Showing the most recent 10 out of 18 publications