Mechanism of Cerebral β‐Amyloid Angiopathy: Murine and Cellular Models

Abstract

Cerebral amyloid angiopathy of the β‐amyloid type (Aβ‐CAA) is a risk factor for hemorrhagic stroke and independently is believed to contribute to dementia. Naturally occurring animal models of Aβ‐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 Aβ‐amyloidosis in humans, develop either Aβ‐CAA only or both Aβ‐CAA and parenchymal amyloid, or primarily parenchymal amyloid with only scarce Aβ‐CAA. The lessons learned from these mouse models are: i) Aβ‐CAA alone is sufficient to induce cerebral hemorrhage and associate pathologies including neuroinflammation, ii) the origin of vascular amyloid is mainly neuronal, iii) Aβ‐CAA results largely from impaired Aβ clearance, iv) a high ratio Aβ40:42 favors vascular over parenchymal amyloidosis, and v) genetic risk factors such as ApoE modulate Aβ‐CAA and CAA‐induced hemorrhages. Therapeutic strategies to inhibit Aβ‐CAA are poor at the present time. Once Aβ‐CAA is present current Aβ 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 Aβ‐CAA, with these first generation mouse models of Aβ‐CAA, refining these models is needed and will help to understand the emerging importance of Aβ‐CAA for dementia and to develop biomarkers and therapeutic strategies.