Simple SummaryAmyloid Transthyretin (ATTR) amyloidosis results from the aggregation of liver-derived transthyretin within the heart and nervous system. Herein, we further define the properties of our recently described monoclonal antibody targeting misfolded TTR. We show that the antibody binds both soluble as well as aggregated insoluble forms of TTR, thus addressing two triggering forms of the protein independently mediating neurotoxicity. Furthermore, we show that the antibody enhances the clearance of aggregated TTR via microglia and protects neurons from misfolded-TTR-mediated toxicity. These two complementary protective mechanisms are evident by the ability of the antibody to protect from experimental neuropathy inducible by misfolded TTR infiltrated into the sciatic nerves of rats. The findings of the study suggest that the approach of amyloid debulking may stand as a promising strategy for disease modification in patients with ATTR polyneuropathy.ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia.