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

Abstract

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.

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

“…TLR2/3 deficiency attenuated the Aβ-induced changes in microglia. Consistently, our data have indicated that Aβ-induced increase in production of inflammatory cytokines was inhibited by pre-treating microglia with an anti-TLR2 antibody [16] and, interestingly, anti-TLR2 antibody prevented the Aβ-induced decrease in long-term potentiation (LTP), correlating with the evidence that the interaction of Aβ with TLR2 is associated with impaired cognition [14]. The evidence also indicates that administration of anti-TLR2 antibody to APP/PS1 mice improves cognitive function and this is associated with a decrease in microglial activation and with a decrease in Aβ accumulation, suggesting that it may affect phagocytosis [17].…”

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…Furthermore, these neuroprotective actions of naloxone were not limited to LPS, as (ϩ)-naloxone, (Ϫ)-naloxone, and naloxone methiodide all protected against ␤-amyloid-induced neurotoxicity and superoxide formation by microglia (Liu et al, 2002b). It is noteworthy that there is significant evidence that ␤-amyloid can activate microglia via TLR4-dependent pathways (Tang et al, 2008;Reed-Geaghan et al, 2009;Vollmar et al, 2010), suggesting, given the previously discussed evidence, that naloxone has nonstereoselective cross-ligand sensitivity of action at TLR4.…”

Exogenous Administration of PACAP Alleviates Traumatic Brain Injury in Rats through a Mechanism Involving the TLR4/MyD88/NF-κB Pathway

“…Among them, TLR4 is widely expressed in the brain and can detect endogenous agonists, such as the degradation products of macromolecules, heat shock proteins 60 and 70, and intracellular components of ruptured cells ( Johnson et al, 2003). TLR4 has been shown to participate in the cerebral inflammatory response related to ischemia reperfusion injury (Arslan et al, 2010;Brea et al, 2010), TBI ), Alzheimer's disease (Ding et al, 2011;Vollmar et al, 2010), and Parkinson's disease (Panaro et al, 2008;Waak et al, 2009). The TLR4 signaling pathway is mediated by interaction with the adapter protein myeloid differentiation factor 88 (MyD88), which leads to activation of nuclear factor-kappa B (NF-jB), and subsequent production of proinflammatory cytokines (Pulskens et al, 2008;Stetler et al, 2010).…”