This paper gets to the issue of vascular dementia. Cerebral amyloid angiopathy, in which Aβ released from neurons settles on blood vessels, can be generated in transgenic mice. The APP23 mice used here, for example, develop CAA (see transgenic mice directory) in addition to depositing plaques in the brain’s parenchyma. The authors write that 80 percent of people with AD also have CAA, yet the broader issue of how vascular pathology relates to AD pathogenesis remains poorly defined. (Interestingly, some human hereditary Aβ mutations cause severe CAA; see Dominic Walsh’s review.) In addition, this paper provokes thought because passive immunization is sometimes considered safer than active immunization.

In this study, Pfeifer et al. immunized 10 aged APP23 mice (which have CAA), and 12 young APP23 mice (which do not) with a monoclonal antibody recognizing amino acids 3 to 6 of Aβ42 once a week for five months. Confirming prior work in the field, the treatment did reduce the number of diffuse Aβ deposits and lowered brain Aβ42 content as measured by ELISA. However, it also doubled the frequency of CAA-associated hemorrhages and made them more severe. Immunized mice had six acute hematomas, while control mice had one. This did not happen in the young mice. Prior mouse Aβ immunization studies did not find this side effect, the authors note.

The researchers suggest that the micro-infarcts could occur if the antibody binding to amyloid in the vessel wall caused a local inflammatory reaction that further weakened the vessel wall beyond the damage already done by amyloid deposition alone. An alternative mechanism might be that antibody binding to soluble Aβ in the blood somehow increases the vessel wall’s permeability.

Whatever the mechanism proves to be, the scientists suggest that their finding might be relevant to the inflammation reported in the discontinued Elan trial (see live chat), and recommend that second-generation immunization strategies be developed using mouse models that also have CAA in order to avoid this potential problem.-Gabrielle Strobel.

Reference:Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral Hemorrhage after Passive Anti-Ab Immunotherapy. Science 2002, Nov 15, 1379. Abstract