Abstract
Hereditary ATTR V30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by deposition of aberrant transthyretin (TTR). Immunohistochemical examination of sural nerve biopsies in patients with amyloidotic neuropathy show co-aggregation of TTR with several proteins; including apolipoprotein E, serum amyloid P and components of the complement cascade. Complement activation and macrophages are increasingly recognized to play a crucial role in amyloidogenesis at the tissue bed level. In the current study we test the effect of two C5a receptor agonists and a C5a receptor antagonist (PMX53) on disease phenotype in ATTR V30M mice. Our results indicate that amyloid deposition was significantly reduced following treatment with the C5a receptor agonists, while treatment with the antagonist resulted in a significant increase of amyloid load. Administration of the C5a receptor agonists triggered increased recruitment of phagocytic cells resulting in clearance of amyloid deposits.
Highlights
Hereditary ATTR V30M amyloidosis is a life-threatening progressive sensory-motor and autonomic peripheral neuropathy
We have recently demonstrated that C1q deficient ATTR V30M mice exhibit a 60% increase in amyloid deposition compared to their C1q efficient counterparts (Panayiotou et al, 2017)
Our results show that ELANE is highest in the group of mice treated with the full agonist molecule, which retains its anaphylactic properties, while it is lower in the group treated with the agonist EP67 which activates C5aR receptors on macrophages but less so on neutrophils (Figure 3B)
Summary
Hereditary ATTR V30M amyloidosis is a life-threatening progressive sensory-motor and autonomic peripheral neuropathy. ATTR V30M amyloidosis is caused by extracellular accumulation of misfolded transthyretin (TTR), subsequently creating insoluble aggregates of amyloid fibrils (Saraiva et al, 1984). Even though there are more than a 100 mutations causing ATTR amyloidoses, the first discovered and by far the most common is ATTR V30M, which is due to a substitution of a valine with methionine in position 30 (Val30Met) of the TTR protein ( Ando et al, 2005). There is considerable variability in the age of onset and penetrance of hereditary ATTR V30M in different countries. Epigenetic and genetic factors are believed to contribute to this variability. Complement cascade components have been shown to co-precipitate with amyloid in various
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