Toll-like receptors, essential pattern-recognition receptors (PRRs) of the innate immune system,
recognize a range of conserved molecules of invading pathogens. Among them, TLR4 is expressed on
the cell surface on both hematopoietic and non-hematopoietic cells, including cells of the central nervous
system, playing a crucial role in both innate and neuroimmune responses. It is the receptor of LPS
(Lipopolysaccharide) endotoxins, the major outer membrane components of Gram- bacteria and a potent
activator of innate immunity and inflammatory response, inducing the expression of the proinflammatory
molecules IL-18 and TNF-\u3b1.
Recently, amyloidogenesis has been identified as new player in innate immune responses and has been
proposed as a detoxifying event to fight ROS (reactive oxygen species) increase, given that an excessive
oxidative stress becomes harmful to cells when their antioxidant capacities result insufficient to retain
the appropriate redox state. Thus, an uncontrolled activation of the innate immune system can lead to
amyloid fibrils accumulation and chronic inflammation. In addition, it has been shown that LPS and
TLR4 are associated with Alzheimer disease (AD), characterized by the accumulation of amyloid fibrils
and neuroinflammation.
Within this context, microglia in the brain and monocytes/neutrophils in the periphery have a prominent
role in initiating and regulating inflammation processes.
Here we propose the use of the medicinal leech, Hirudo verbana, as a powerful model system to
understand the role of TLR4 in innate immune response and neuroimmune activation. The advantages of
using this model is found in its innate immune system that is very similar to Vertebrate\u2019s one, but lacking
the complex cross-talk typical of adaptive immunity. Our in vivo and in vitro approaches, by means of
histological, ultrastructural, immunohistochemical and Western Blot techniques aim to correlate amyloid
fibrils and ROS production with LPS treatment, clarifying the relationship between peripheral and central
nervous system immune responses. Furthermore, by blocking TLR4 intracellular cascade we
demonstrate that both macrophages and microglia cells undergo to a rescue process that implicate
amyloid fibrils degradation and restoration of physiological conditions.
In conclusion, our study is promising to gain novel insight about the correlation between peripheral/neuro
inflammation and amyloid accumulation
