title: Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates.
abstract: Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of transthyretin (TTR) amyloid fibrils, particularly in the peripheral nervous system. No systematic immunohistochemical data exists relating TTR deposition with FAP progression. We assessed nerves from FAP patients in different stages of disease progression (FAP 0 to FAP 3) for TTR deposition by immunohistochemistry, and for the presence of amyloid fibrils by Congo Red staining. The nature of the deposited material was further studied by electron microscopy. We observed that early in FAP (FAP 0), TTR is already deposited in an aggregated nonfibrillar form, negative by Congo Red staining. This suggested that in vivo, preamyloidogenic forms of TTR exist in the nerve, in a stage before fibril formation. Cytotoxicity of nonfibrillar TTR was assessed in nerves of different FAP stages by immunohistochemistry for macrophage colony-stimulating factor. FAP 0 patients already presented increased axonal expression of macrophage colony-stimulating factor that was maintained in all other stages, in sites related to TTR deposition. Toxicity of synthetic TTR fibrils formed in vitro at physiological pH was studied on a Schwannoma cell line by caspase-3 activation assays and showed that early aggregates but not mature fibrils are toxic to cells. Taken together, these results show that nonfibrillar cytotoxic deposits occur in early stages of FAP.
authors.affiliation: Institute for Cellular and Molecular Biology, Porto, Portugal.
authors.forename: M M
authors.initials: MM
authors.lastname: Sousa
authors.forename: I
authors.initials: I
authors.lastname: Cardoso
authors.forename: R
authors.initials: R
authors.lastname: Fernandes
authors.forename: A
authors.initials: A
authors.lastname: Guimarães
authors.forename: M J
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D000293:Adolescent; D000328:Adult; D000682:Amyloid / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008854:Microscopy, Electron; D008875:Middle Aged; D011228:Prealbumin / Q000378:metabolism* / Q000494:pharmacology / Q000648:ultrastructure; D013497:Sural Nerve / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D011228:Prealbumin; D016173:Macrophage Colony-Stimulating Factor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases