Apart from the mostly rare amyloid neuropathies described above, some common acquired diseases also are associated with peripheral neuropathy and amyloid. However, little is known about the potential contribution of the amyloidogenic protein in the pathogenesis of peripheral neuropathy in these diseases, and these diseases are not (yet) classified as peripheral amyloid neuropathies. The possible causative relation of amyloid and toxic oligomers with peripheral neuropathy in these diseases will be discussed next, with a specific focus on type 2 diabetes mellitus.
3.2.1. Type 2 Diabetes Mellitus (T2DM)
In 2019 the International Diabetes Federation (IDF) indicated that there were ~450 million people with DM worldwide. This number is expected to rise to 700 million by 2045 [55
]. Type 1 DM is characterized by autoimmune-mediated loss of the insulin-producing β-cells in the pancreatic islets of Langerhans, causing insulin insufficiency and hyperglycemia [118
]. T2DM is the most common type of DM, accounting for approximately 90% of all DM patients [55
]. T2DM is characterized by both insulin resistance (reduced insulin sensitivity of insulin target tissues as a consequence of obesity) and β-cell failure (insulin insufficiency), leading to hyperglycemia. Increased β-cell apoptosis in T2DM is associated with glucotoxicity, lipotoxicity, and deposition of amyloid in the pancreatic islets [119
]. Islet amyloid is a characteristic histopathological feature of T2DM, being detected in approximately 90% of T2DM patients at autopsy [24
]. However, islet amyloid has recently also been detected in 3 young patients with T1DM [122
Peripheral neuropathy is the most frequent chronic complication of DM. The prevalence of peripheral neuropathy in DM ranges from 10% at one year after DM diagnosis to more than 50% during progression of the disease [4
], making diabetic peripheral neuropathy (DPN) the most abundant type of peripheral neuropathy worldwide [3
] (Table 1
). Diabetic neuropathy that is painful develops in approximately 50% of DM patients with neuropathy [126
]. DPN is a major cause of lower limb amputation, which severely affects both quality of life and life expectancy [127
]. Peripheral neuropathy in T2DM is poorly managed clinically because of its late diagnosis, complex pathogenesis, and the limited therapeutic options to treat neuropathy [4
]. Long-lasting DM causes loss of sensory peripheral nerve terminals. At the early stage of DPN, small nociceptive sensory fibers are commonly affected. Motor function is hardly affected, although some slowing of motor conduction velocity is observed [128
]. The symptoms of DPN involve gain- or loss-of-function, depending on the type of nerve that has been damaged. Gain-of-function symptoms include allodynia (feeling of pain from non-painful stimuli) and hyperalgesia (increased pain sensitivity), whereas loss-of-function symptoms include tactile and thermal hyposensitivity [3
]. Patients can experience pain in some areas of the body and loss of sensitivity in other areas [3
]. During progression of DPN, patients can even develop a total loss of sensation (numbness), which contributes to development of complications such as diabetic foot ulcers [25
]. The symptoms of DPN tend to follow a “stockings and gloves” pattern, which means that they start at the feet and hands [3
Hyperglycemia is generally considered a primary cause of DPN [3
]. Several hyperglycemia-induced molecular pathways contribute to deregulation of neuronal function, including the polyol pathway, hexosamine pathway, activation of PKC isoforms (notably α, β1, β2, δ, and ε), and formation of advanced glycation end products (AGEs), among others [3
]. These pathways and molecules cause microangiopathy, oxidative stress, and inflammation, which contribute to cytotoxic effects on neurons and Schwann cells, leading to nerve fiber loss and axonal degeneration, and consequently loss of sensory perception (reviewed in [130
]). However, some data indicate that other factors besides hyperglycemia play a role in the development of DPN in T2DM. For example, tight blood glucose control is able to reduce hyperglycemia and diminish neuropathy in T1DM [135
], but in T2DM improved glycaemia is not, or only partly, accompanied by less severe neuropathy [135
]. Moreover, neuropathy is also present in individuals with prediabetes (i.e., not yet having developed hyperglycemia) [137
], indicating factors other than hyperglycemia are involved. Large clinical studies support the concept that components of the metabolic syndrome, (notably obesity and prediabetes) which include elevated levels of the amyloidogenic protein hIAPP, may underlie the pathogenesis of DPN, especially in T2DM [138
IAPP is the fibril-forming protein of pancreatic islet amyloid, which is composed of 37 amino acids and is co-produced and co-secreted with insulin from the pancreatic islet β-cells [36
]. The physiological functions of IAPP are not fully understood, but include enhancement of satiety, reduction of gastric emptying and of glucagon release, and inhibition of insulin signaling [36
]. Insulin resistance leads to increased production of insulin to compensate for its impaired signaling, which is accompanied by increased production of IAPP [35
]. Moreover, free fatty acid levels in the blood increase with obesity, promoting IAPP gene expression and secretion by islet β-cells [141
]. Elevated concentrations of human IAPP (hIAPP) trigger formation of toxic oligomers and amyloid plaques, which impair islet function and increase β-cell apoptosis [24
]. In contrast to hIAPP and IAPP from monkeys and cats, murine and rat IAPP are not amyloidogenic due to differences in the amino acid sequence [143
]. Therefore, rodent models with islet β-cell-specific expression of a hIAPP transgene have been developed to study the pathogenic role of hIAPP and islet amyloidosis [145
]. In T2DM, deposits of aggregated hIAPP are found in the pancreatic islets, but also elsewhere in the body, i.e., in the heart, kidneys, and brain [146
], indicating that amyloidosis in T2DM is not restricted to the pancreas. Apart from the pancreatic islet β-cells, IAPP is also expressed in peptidergic sensory neurons [149
]. Several mouse studies revealed that IAPP has an excitatory role in nociception [150
]. Therefore, with the knowledge that several other amyloid proteins cause peripheral neuropathy, we hypothesized that aggregated hIAPP causes peripheral neuropathy in individuals where hIAPP is overproduced, as is the case in (development of) T2DM.
Injection of hIAPP in wild-type mice induces mechanical hypersensitivity and reduction in nerve fiber density [156
]. More importantly, in a more physiologically relevant model system, i.e., transgenic mice endogenously expressing hIAPP specifically in pancreatic islet β cells [142
], mechanical hypersensitivity develops and skin nerve fibers are reduced [156
]. Thus, hIAPP causes signs of peripheral neuropathy in vivo, even in the absence of hyperglycemia. In further support of hIAPP as a driver of painful neuropathy, others reported that IAPP modulates neuropathic pain in mice and rats at different levels of the nervous system [154
]. Moreover, hIAPP is involved in central neuropathy, both in Alzheimer’s disease patients with T2DM [159
] and in diabetic hIAPP transgenic rats [159
], further substantiating the neuropathic potential of aggregated hIAPP. Overall, these data support the hypothesis that hIAPP is a driver of peripheral neuropathy in T2DM, but since the clinical data are only correlative, further investigation into the role of hIAPP in peripheral neuropathy in human T2DM is warranted.
3.2.2. Acquired Chronic Inflammatory Diseases
Serum amyloid A protein amyloidosis (SAA) is a major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Serum amyloid A protein is synthetized in large quantities in chronic inflammatory diseases and can lead to amyloid deposits in any chronic inflammatory disorder [161
]. Amyloid deposits are mainly found in kidney, subcutaneous adipose tissue, and gastrointestinal mucosa. Peripheral neuropathy is not considered as a characteristic feature of this systemic amyloid disease. However, in several chronic inflammatory diseases, notably in rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and to a lesser extent inflammatory bowel diseases, peripheral neuropathy is present in a subset of patients, and amyloid has been demonstrated in these diseases [58
] (see Table 1
). For example, in sural nerve biopsies of rheumatoid arthritis patients, perineurial thickening with amyloid was detected in 4 out of 23 patients investigated [163
]. In knee joints of 12 out of 12 osteoarthritis patients, as well as 7 out of 12 aged individuals without osteoarthritis, amyloid was present in menisci, articular cartilage, and synovial membranes, mostly of TTR and Apo-AI origin [164
]. In psoriatic arthritis, amyloid has been reported in 30 cases and was present mainly in the kidney [166
]. In Crohn’s disease, SAA-protein-derived amyloid is found in the kidney and gastrointestinal tract in 0.3–10% of patients [167
Whether there is a causal relation between the development of peripheral neuropathy and amyloid in these diseases is not known, because literature on peripheral nervous system involvement in inflammation-related amyloidosis is scarce. However, three cases reports of patients with peripheral neuropathy and SAA protein amyloid exclusively within axons and myelin sheaths underscore a potential link between SAA amyloid and peripheral neuropathy [78
]. Thus, amyloid protein aggregation might also be involved in development of peripheral neuropathy in chronic inflammatory diseases.
The presence of amyloid in histological specimens is routinely demonstrated by Congo red staining of tissue sections and subsequent yellow-green birefringence when viewed with polarized light (see Figure 3
). The reported prevalence of amyloid detected with this method within the peripheral nervous system in T2DM and chronic inflammatory diseases is low, or has even not been investigated or reported at all. However, this technique only detects fibrillary amyloid deposits, not prefibrillar aggregates such as oligomers. Notably, these oligomers are generally thought to be the most cytotoxic species of amyloid protein aggregates. In addition, amyloid deposits are generally larger, and thus more readily detectable in organs such as the kidney and heart as compared to nerves or even individual neurons. We propose that pathogenic involvement of amyloid protein aggregation in peripheral neuropathy may be underestimated in some diseases not (yet) considered as amyloid neuropathies.
As peripheral sensory neuropathy is a hallmark of several amyloidoses, T2DM, and some inflammatory diseases, the question arises as to why sensory neuropathy is most prominent in these diseases. Damage to peripheral sensory nerves may be noticed or diagnosed sooner as compared to other nerves. Nevertheless, peripheral neurons, in particular long axons, may be particularly sensitive to degeneration and to toxic compounds due to their effects on key processes essential to maintaining homeostasis in these long axons, such as protein transport, membrane integrity, and mitochondrial function. Some sensory neurons are not covered by myelin sheets, which may render them even more susceptible. Finally, sensory neurons may have a particular sensitivity towards oligomers because of the composition of plasma membrane lipids, which might promote oligomer toxicity. Although these aspects may contribute to the observed presence of neuropathy in amyloidosis, future research will have to address these issues.
To further support potential links between amyloid or toxic oligomers and the development of peripheral neuropathy in these diseases, we will discuss the mechanisms as to how amyloid and amyloid protein aggregates may contribute to peripheral neuropathy.