Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy

Koike, Haruki; Ikeda, Shohei; Takahashi, M; Kawagashira, Yuichi; Iijima, Masahiro; Misumi, Yohei; Ando, Yumiko; Ikeda, Shu Ichi; Katsuno, Masahisa; Sobue, Gen

doi:10.1212/wnl.0000000000003362

Cited by 92 publications

(120 citation statements)

References 39 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…A previous study showed extensive nerve fiber loss despite small amount of amyloid deposition in late-onset FAP patients from non-endemic areas, indicating that pre-fibrillar TTR aggregates may participate in fiber degeneration in such patients [47]. In contrast, a recent study indicated that direct insult of amyloid fibrils caused Schwann cell damage, leading to nerve fiber loss, in early-onset FAP patients from endemic foci [48]. All together, these data contributes to the hypothesis that also macrophage phenotype and function may be differently modulated depending on the onset and patient endemic area.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Gonçalves

Moreira

Martins

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundIncreasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown.MethodsIn this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems.ResultsWe show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naïve peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype.ConclusionAltogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues—the peripheral nerve and the gastrointestinal tract.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0891-9) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Gonçalves

Moreira

Martins

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Interestingly, loss of tight junctions and the fenestration of endothelial cells, as well as other changes in endotelial cell mophology and number, were recently identified as common pathological finding by electron microscopy in sural nerve biopsies from patients with ATTR amyloidosis. 7 Of note, spondilogenic radiculopathies and lumbar canal stenosis were also frequently suspected before the diagnosis of ATTR amyloidosis and a not negligible proportion of these patients underwent spine surgery with partial or no benefit. These data should encourage to raise awareness in neurosurgeons and orthopaedic surgeons about the possibility of ATTR amyloidosis in patients with sensory disturbances and progressive motor deficit at lower limbs, particularly in association with bilateral carpal tunnel syndrome.…”

mentioning

confidence: 99%

Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy

Cortese

Vegezzi

Lozza

et al. 2017

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

“…50 In a study of 165 ATTRm amyloidosis patients carrying the mutation Val30Met, HRV was reduced in 47%. 53 Additionally, Schwann cell atrophy and disruption of the blood-nerve barrier can be found. Biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy.…”

Section: Autonomic Testingmentioning

confidence: 99%

Hereditary transthyretin-related amyloidosis

et al. 2018

View full text Add to dashboard Cite

Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early-and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat-and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal). K E Y W O R D Samyloid, neuropathy, small fiber, tafamidis, transplantation, transthyretin | 93 FINSTERER ET al. eyes, the gastrointestinal tract, the kidneys, and the skin. ATTRm amyloidosis is resistant to immunotherapy. Though ATTRm-related polyneuropathy or TTR-CA may occur without affection of another tissue, a variable combination of organ affection (multiorgan involvement) is the most frequent phenotype. This review aims at summarizing and discussing previous and recent findings concerning the clinical presentation, genetic background, pathogenesis, diagnosis, treatment, and outcome of ATTRm-related polyneuropathy. | ME THODSData for this review were identified by searches of MEDLINE for references of relevant articles. Search terms applied were "transthyretin," "gene," "TTR-FAP," or "mutation," combined with "neuropathy," "hereditary," "autonomic," "small fiber neuropathy," and "polyneuropathy." Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were randomized controlled trials (RCTs), observational studies with controls, case series, and case reports. Only original articles about humans, and published between 1966 and 2018 were included. Reviews, editorials, and letters were not considered. Reference lists of retrieved studies were checked for reports of additional studies. Websites checked for additional, particularly geneti...

show abstract

Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy

Cited by 92 publications

References 39 publications

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy

Hereditary transthyretin-related amyloidosis

Contact Info

Product

Resources

About