. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5048-53. PubMed.

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  1. This is a very interesting paper from Monsonego and colleagues. It provides us with another potential mechanism for the meningoencephalitis observed in the Aβ vaccination clinical trial. The two factors that appear critical to the development of meningoencephalitis in these experiments are the MHC class II haplotype and brain levels of IFN-γ. Also, the removal of amyloid in APP+IFN-γ transgenic mice appears to be antibody-independent as no titers were developed.

    The authors show that T cell proliferation following a single Aβ1-42 immunization in SJL mice with the I-As MHC-II haplotype is over 10-fold greater than in C57BL6 mice with the I-Ab haplotype. Also, different Aβ fragments stimulate T cell proliferation when different MHC-II haplotypes are present. This suggests that the HLA haplotype of the patient could act as a predictor for the development of meningoencephalitis in response to Aβ vaccination.

    Aβ vaccination of APP+IFN-γ transgenic mice on an SJL background results in marked meningoencephalitis only 12 days following immunization. Importantly, the IFN-γ transgene is under the control of the myelin-basic protein promoter, ensuring only CNS expression. The time course of this T cell infiltration is extremely interesting, as it shows that by day 20, the CD4 and Cd11b cells have moved from the meningeal tissue to the parenchymal plaques in the hippocampus. By day 60, no infiltrates were observed, suggesting the meningoencephalitis is transient. Hippocampal tissue close to the area of infiltration in the APP+IFN-γ transgenic mice shows significant activation of microglia and reduced levels of compact amyloid. These mice did not develop antibody titers, suggesting that the amyloid removal is antibody-independent and instead associated with the T cell response. This suggests a novel mechanism of amyloid removal in response to active vaccination. The IFN-γ is critical to the development of meningoencephalitis, as the single APP transgenic mice did not show T cell infiltrates. It would be interesting to see if administration of another immunization would result in new infiltration and whether this would be more severe than observed following the first dose.

    These data highlight the necessity of characterizing the role of inflammation in Alzheimer disease. This is now more important than ever since we are developing new, disease-modifying therapies, the efficacy of which could depend on the inflammatory state in the brain.

    View all comments by Donna M. Wilcock

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