Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), commonly referred to as “amyloid neuropathy,” is one of the most severe peripheral neuropathies. After disease onset, patients experience progressive limb weakness, sensory loss, and autonomic dysfunction, which usually leads to death within just a few years. Amyloid neuropathy is a rare autosomal dominant hereditary disease caused by mutations in the transthyretin (TTR) gene. TTR is a transport protein produced in the liver and circulated through the blood. Gene mutations cause misfolding of the protein product, resulting in the dissociation of its naturally formed tetramers and subsequent aggregation into amyloid deposits. Amyloid deposits can be observed in patients’ nervous tissues and organs; however, how these mutated proteins cause neurodegeneration remains an unsolved mystery, hindering the development of precise therapeutic strategies. In Taiwan, as many as 90% of patients have a mutation in which the 97th amino acid of TTR changes from alanine (A) to serine (S), known as TTR-A97S. This differs from most patients in Europe, the United States, and Japan, who typically carry the V30M mutation. Moreover, disease onset in Taiwanese patients generally occurs around the age of 50, which is later than the onset age for V30M. Recognizing the importance of safeguarding public health, Professor Sung-Tsang Hsieh and colleagues at NTU have dedicated more than 20 years to studying the pathogenic mechanisms of TTR-A97S.

In this study, the researchers found that protein levels in the cerebrospinal fluid of TTR-A97S patients were elevated and negatively correlated with nerve density, indicating leakage of the blood-nerve barrier, thereby causing neurodegeneration. Examination of thin nerve sections from patients revealed that the tight junctions between endothelial cells of microvessels were disrupted, leading to amyloid deposition around blood vessels. This demonstrates that the blood-nerve barrier is damaged by mutant TTR proteins, allowing them to leak out and accumulate as amyloid. This leakage phenomenon further triggers inflammatory responses and neurodegeneration. Infiltration of large numbers of macrophages was observed in patient nerve sections, some of which were polarized into M1 macrophages that released abundant cytokines, thereby exacerbating neuroinflammation. The same neuroinflammatory responses were also observed in transgenic mice carrying the TTR-A97S mutation. From clinical findings to animal models, the results demonstrate that mutant TTR proteins induce neuroinflammation and cause neurodegeneration. This newly discovered pathogenic mechanism provides a new direction for developing therapeutic strategies for amyloid neuropathy.