Chapter 2 - Genetic Animal Models of Cerebral Vasculopathies

Abstract

Cerebral amyloid angiopathy (CAA) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are genetic cerebrovasculopathies associated with neurodegeneration and vascular cognitive impairment. Linked to autosomal dominant mutations in diverse genes that encode cell-surface receptors (i.e., amyloid precursor protein in CAA and NOTCH3 in CADASIL), both diseases are associated with accumulation of abnormal material around cerebral vessels, such as amyloid in CAA or granular osmiophilic material in CADASIL. Both CAA and CADASIL share clinical features of white matter degeneration and infarcts, and vascular dementia in the human adult; microbleeds occur in both CADASIL and CAA, but large intracerebral hemorrhages are more characteristic for the latter. While the mechanisms are poorly understood, wall thickening, luminal narrowing, and eventual loss of vascular smooth muscle cells are overlapping pathologies involving leptomeningeal, and pial or penetrating small arteries and arterioles in CAA and CADASIL. Dysregulation of cerebral blood flow and eventual hypoperfusion are believed to be the key pathophysiological steps in neurodegeneration and cognitive impairment. Although animal models expressing CAA or CADASIL mutations have partially reproduced the human pathology, there has been marked heterogeneity in the phenotypic spectrum, possibly due to genetic background differences among mouse models, and obvious species differences between mouse and man. Here, we provide an overview of animal models of CAA and CADASIL and the insight on molecular and physiological mechanisms of disease gained from these models.