Cellular and Molecular Biology


Cerebral ß-amyloid angiopathy in aged squirrel monkeys

H.A. Elfenbein1, R.F. Rosen1, S.L. Stephens1, R.C. Switzer3, Y. Smith1,2, J. Pare1, P.D. Mehta4, R. Warzok5 and L.C. Walker1,2

1Yerkes National Primate Research Center and 2Department of Neurology, Emory University, Atlanta, USA, 3Neuroscience Associates, Knoxville, USA, 4New York State Institute for Basic Research, Staten Island, NY, USA and 5Department of Pathology, University of Greifswald, Greifswald, Germany

Offprint requests to: Lary C. Walker, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA. e-mail: lary.walker@emory.edu

Summary. Cerebral ß-amyloid angiopathy (CAA) is an age-related disorder of the brain vasculature that is involved in up to 20% of non-traumatic cerebral hemorrhage in humans. CAA is a risk factor for cognitive decline, and may exacerbate the dementia of Alzheimer's disease. Progress in discovering the cause and potential therapies for this disorder has been hindered by the paucity of animal models, particularly models of idiopathic CAA. The squirrel monkey (Saimiri spp) develops significant CAA in the natural course of aging. To evaluate the suitability of Saimiri as a model of human CAA, we studied the distribution and composition of Aß subtypes in CAA and parenchymal (senile plaque) deposits in the brains of aged squirrel monkeys, as well as the relationship between vascular ß-amyloid deposition and comorbid vasculopathies that occur in aged humans. Our findings show that: 1) CAA consists ultrastructurally of classical amyloid fibrils and is the principal type of cerebral ß-amyloidosis in squirrel monkeys; 2) The two primary isoforms of Aß (Aß40 and Aß42) coexist in most microvascular and parenchymal lesions of Saimiri, although Aß40 tends to predominate in larger arterioles; 3) CAA and parenchymal plaques overlap to a considerable degree in most affected brain areas, and are distributed symmetrically in the two hemispheres; 4) Both CAA and plaques are particularly abundant in rostral regions and comparatively sparse in the occipital lobe; 5) Capillaries are especially vulnerable to CAA in squirrel monkeys; and 6) When CAA is severe, it is associated with a small, but significant, increase in other vasculopathies, including microhemorrhage, fibrinoid extravasation and focal gliosis. These findings, in the context of genetic, vascular and immunologic similarities between squirrel monkeys and humans, support the squirrel monkey as a biologically advantageous model for studying the basic biology of idiopathic, age-related CAA, and for testing emerging therapies for human ß-amyloidoses such as Alzheimer's disease. Histol Histopathol 22, 155-167 (2007)

Key words: Alzheimer, Apolipoprotein E, Inflammation, Hemorrhage, Vascular dementia

DOI: 10.14670/HH-22.155