Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”.
Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM), of which the pathogenesis is not fully understood. We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth. Transgenic hIAPP Ob/Ob mice, an established animal model for T2DM, as well as hIAPP mice, which have elevated plasma hIAPP levels but no hyperglycaemia. Both transgenic mice developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fibers (IENF), suggesting hIAPP is a mediator of diabetic neuropathy. Intraplantar and intravenous hIAPP injection in WT mice induced long-lasting mechanical hypersensitivity and reduced IENF, whereas non-aggregating murine IAPP or mutated hIAPP (Pramlintide) did not have these effects, and were not toxic for cultured sensory neurons. In T2DM patients, significantly more hIAPP oligomers were found in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP is toxic to sensory neurons, and mediates peripheral neuropathy in mice. The presence of hIAPP aggregates in skin of humans with T2DM supports the notion that human IAPP is a potential driver of T2DM neuropathy in man.
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