TLR4 in Neurodegenerative Diseases: Alzheimer’s and Parkinson’s Diseases

Abstract

A role of inflammation in the pathogenesis of neurodegenerative disorders is commonly accepted. The excess of inflammatory factors production significantly contributes to neuronal dysfunction transforming the original protective function of glial cells in detrimental activities. This general mechanism is differently activated in each single disorder, and specific elements, biological pathways, and timing are combined to affect neuronal vulnerability. The delucidation of the sequence of events at the molecular level might indicate appropriate pharmacological tools to control inflammation with a potential therapeutic meaning. In this chapter, we analyze the role of toll-like receptor 4 (TLR4) as mediator of inflammatory response in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In both pathological conditions the activation of TLR4 has been associated either to harmful or beneficial effects although the data supporting the negative consequence are prevailing. Numerous in vitro and in vivo studies indicate directly or indirectly interaction between the activation of TLR4 and the presence of β-amyloid. Accordingly, in our hands, the memory damage and inflammatory effects obtained by intraventricular application of β-amyloid oligomers were antagonized by TLR4 inhibitor and completely abolished in TLR4-knockout mice. Genetic studies associate missense mutation that attenuates the TLR4 signaling with a reduction of risk to develop AD. The beneficial effects of TLR4 in PD was shown in an experimental model where its ablation hampered the ability of microglia to phagocytize α-synuclein in vitro. In several other experimental conditions, the activation of TLR4 exacerbated the pathological outcomes, and the inhibition attenuated them. In contrast with the data obtained with β amyloid oligomers, the intraventricular application of α-synuclein oligomers was not influenced by TLR4 inhibition or ablation. A possible role of TLR4 has been proposed in the relationship between gut microbiota dysbiosis and increased risk of developing PD. In conclusion, the modulation of TLR4 is an interesting pharmacological target for both AD and PD and some data in these senses has been already shown; however, the relevance of physiological role of TLR4 must be carefully considered for any clinical application.