First Author | Vollmar P | Year | 2010 |
Journal | J Immunol | Volume | 185 |
Issue | 10 | Pages | 6338-47 |
PubMed ID | 20943998 | Mgi Jnum | J:165632 |
Mgi Id | MGI:4837949 | Doi | 10.4049/jimmunol.1001765 |
Citation | Vollmar P, et al. (2010) Active Immunization with Amyloid-{beta} 1-42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System. J Immunol 185(10):6338-47 |
abstractText | Active immunization with amyloid-beta (Abeta) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Abeta(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Abeta(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Abeta(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Abeta(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Abeta(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Abeta(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Abeta(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Abeta(1-42)/CFA. Thus, this study identifies adjuvant effects of Abeta(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Abeta immunotherapy. |