Active Immunization with Amyloid-beta 1-42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

作者：Vollmar Patrick; Kullmann Jennifer S; Thilo Barbara; Claussen Malte C; Rothhammer Veit; Jacobi Hortenzia; Sellner Johann; Nessler Stefan; Korn Thomas^*; Hemmer Bernhard

来源：The Journal of Immunology, 2010, 185(10): 6338-6347.

DOI：10.4049/jimmunol.1001765

Active immunization with amyloid-beta (A beta) 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 A beta(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of A beta(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, A beta(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 A beta(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in A beta(1-42)/CFAimmunized mice were CD11b(+) CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with A beta(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 A beta(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 A beta(1-42)/CFA. Thus, this study identifies adjuvant effects of A beta(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of A beta immunotherapy. The Journal of Immunology, 2010, 185: 6338-6347.

• 出版日期2010-11-15
• 单位河北医科大学