Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models.
Cerebral amyloid angiopathy of the beta-amyloid type (Abeta-CAA) is a risk factor for hemorrhagic stroke and independently is believed to contribute to dementia. Naturally occurring animal models of Abeta-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 Abeta-amyloidosis in humans, develop either Abeta-CAA only or both Abeta-CAA and parenchymal amyloid, or primarily parenchymal amyloid with only scarce Abeta-CAA. The lessons learned from these mouse models are: i) Abeta-CAA alone is sufficient to induce cerebral hemorrhage and associate pathologies including neuroinflammation, ii) the origin of vascular amyloid is mainly neuronal, iii) Abeta-CAA results largely from impaired Abeta clearance, iv) a high ratio Abeta40:42 favors vascular over parenchymal amyloidosis, and v) genetic risk factors such as ApoE modulate Abeta-CAA and CAA-induced hemorrhages. Therapeutic strategies to inhibit Abeta-CAA are poor at the present time. Once Abeta-CAA is present current Abeta 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 Abeta-CAA, with these first generation mouse models of Abeta-CAA, refining these models is needed and will help to understand the emerging importance of Abeta-CAA for dementia and to develop biomarkers and therapeutic strategies.
Herzig
Martin C
MC
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany. martin.herzig@uni-tuebingen.de
Van Nostrand
William E
WE
Jucker
Mathias
M
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009154:Mutation
D016229:Amyloid beta-Peptides