Familial amyloid polyneuropathy (FAP) is an autosomal dominant neurodegenerative disorder related to the systemic deposition of mutated transthyretin (TTR) amyloid fibrils, particularly in peripheral nervous system (PNS). TTR fibrils are diffusely distributed in the PNS of FAP patients, involving nerve trunks, plexuses and ganglia. In peripheral nerves, amyloid deposits are prominent in the endoneurium, near blood vessels, Schwann cells and collagen fibrils. Fiber degeneration is axonal, beginning in the unmyelinated and low diameter myelinated fibers. Several hypotheses have been raised to explain axonal and neuronal loss: (i) compression of the nervous tissue by amyloid; however, a cause-effect relationship between amyloid deposition, structural nerve changes and degeneration was never clearly made; (ii) role of nerve ischemia secondary to lesions caused by perivascular amyloid, which is also doubtful as compromised blood flow was never demonstrated; (iii) lesions in the dorsal root ganglia neurons or Schwann cells. Recently, evidence for the presence of toxic non-fibrillar TTR aggregates early in FAP nerves constituted a first step to unravel molecular signaling related to neurodegeneration in FAP. The toxic nature of TTR non-fibrillar aggregates, and not mature TTR fibrils, was evidenced by their ability to induce the expression of oxidative stress and inflammation-related molecules in neuronal cells, driving them into apoptotic pathways. How these TTR aggregates exert their effects is debatable; interaction with cellular receptors, namely, the receptor for advanced glycation endproducts (RAGE), is a probable candidate mechanism. The pathology and the yet unknown molecular signaling mechanisms responsible for neurodegeneration in FAP are discussed.

中文翻译：

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家族性淀粉样蛋白多神经病的神经退行性变：从病理学到分子信号转导。

家族性淀粉样蛋白多神经病（FAP）是一种常染色体显性遗传性神经退行性疾病，与突变的甲状腺素蛋白（TTR）淀粉样蛋白原纤维的全身沉积有关，特别是在周围神经系统（PNS）中。TTR原纤维散布在FAP患者的PNS中，涉及神经干，神经丛和神经节。在周围神经中，淀粉样蛋白沉积在神经内膜中，血管附近，雪旺氏细胞和胶原纤维中很明显。纤维变性是轴突，始于无髓和低直径的有髓纤维。提出了一些假说来解释轴突和神经元的丧失：（i）淀粉样蛋白对神经组织的压迫；然而，淀粉样蛋白沉积，神经结构改变和变性之间的因果关系从未明确阐明。（ii）由于血管周围淀粉样蛋白引起的病变继发于神经缺血的作用，这也值得怀疑，因为从未证实血流受损；（iii）背根神经节神经元或雪旺氏细胞中的病变。最近，在FAP神经中早期存在有毒非原纤维TTR聚集体的证据构成了揭开与FAP中神经变性相关的分子信号的第一步。TTR非原纤维聚集体（而不是成熟的TTR原纤维）的毒性本质是由它们诱导神经元细胞中氧化应激和炎症相关分子表达，使其进入凋亡途径的能力证明的。这些TTR聚集体如何发挥作用尚有争议；与细胞受体（即晚期糖基化终产物（RAGE）的受体）的相互作用是可能的候选机制。