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

摘要

Active immunization with amyloid-β (Aβ) 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 Aβ1–42 are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ1–42/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55/CFA or CFA alone, Aβ1–42/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 Aβ1–42/CFA-immunized animals. In contrast to MOG35–55/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ1–42/CFA-immunized mice were CD11b+CD14+ and CD45high, indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ1–42/CFA was significantly more potent than immunization with MOG35–55/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 Aβ1–42-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 Aβ1–42/CFA. Thus, this study identifies adjuvant effects of Aβ1–42, which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.