In this month’s Brain, researchers at the Universities of Milan and Genoa, Italy, report that immunizing C57/Bl6 mice with Aβ42 generated an inflammatory response similar to an autoimmune disease in the brains of these mice. None of the prior studies of Aβ42 immunotherapy of various mouse AD models, which were conducted in preparation for clinical trials of this approach, had reported this side effect (see Schenk et al., 1999; Janus et al., 2000; and Morgan et al., 2000). Roberto Furlan, working with Gianvito Martino and colleagues, injected human Aβ42 into six- to eight-week-old female mice, following the dosing regime and schedule as described previously. In a second group of mice, they added pertussis toxin (PT), an immunostimulant known to boost T cell responses and to predispose to autoimmune reactions. Sixteen out of 18 mice in this second group developed a chronic CNS inflammation reminiscent of experimental allergic encephalitis (EAE), a condition in mice widely used to model multiple sclerosis.
The mice showed inflammatory aggregates of macrophages and T cells surrounding small venules in the leptomeningeal space and the brain and spinal cord parenchyma. The authors saw occasional areas of demyelination, though much less widespread than in EAE mice. Mice treated with adjuvant plus PT, but no Aβ, had macrophages but no T cells in these areas. Some of the Aβ- and PT-injected mice had small areas of necrosis in the spleen and gastrointestinal tract. T cells isolated from the lymph nodes of these animals showed a dose-dependent response to stimulation with Aβ and produced cytokines typical of the Th-1 responses seen in autoimmune diseases. Aβ antibodies were present in serum irrespective of pertussis toxin injection. The authors write that the complement-fixing IgG2a antibodies seen in this study were probably pathogenic in the PT-treated mice, but can be beneficial under other circumstances, as in prior studies, where such antibodies triggered microglia into clearing amyloid.
The authors write that the difference between this study and prior work in transgenics hinges on the presence of the pertussis toxin, but they do not discuss how this factor relates to humans. They do conclude, however, that the demonstration of a quasi-autoimmune response against AβPP/Aβ in mice poses a challenge to the idea of Aβ vaccination as a therapy for Alzheimer’s disease.—Gabrielle Strobel
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