Mechanism of cerebral beta-amyloid angiopathy: Murine and cellular models

Cerebral amyloid angiopathy of the beta-amyloid type (A beta-CAA) is a risk factor for hemorrhagic stroke and independently is believed to contribute to dementia. Naturally occurring animal models of A beta-CAA are scarce and not well suited for the laboratory. To this end, a variety of transgenic mouse models have been developed that, similar to cerebral A beta-amyloidosis in humans, develop either A beta-CAA only or both A beta-CAA and parenchymal amyloid, or primarily parenchymal amyloid with only scarce A beta-CAA. The lessons learned from these mouse models are: i) A beta-CAA alone is sufficient to induce cerebral hemorrhage and associate pathologies including neuroinflammation, ii) the origin of vascular amyloid is mainly neuronal, iii) A beta-CAA results largely from impaired A beta clearance, iv) a high ratio A beta 40:42 favors vascular over parenchymal amyloidosis, and v) genetic risk factors such as ApoE modulate A beta-CAA and CAA-induced hemorrhages. Therapeutic strategies to inhibit A beta-CAA are poor at the present time. Once A beta-CAA is present current A beta immunotherapy strategies have failed to clear vascular amyloid and even run the risk of serious side effects. Despite this progress in deciphering the pathomechanism of A beta-CAA, with these first generation mouse models of A beta-CAA, refining these models is needed and will help to understand the emerging importance of A beta-CAA for dementia and to develop biomarkers and therapeutic strategies.