RESEARCH ON THE MOLECULAR MECHANISM UNDERLYING THE TRANSMISSION PHENOMENON IN AMYLOIDOSES INVOLVING HUMAN NEUROLOGICAL SYSTEMS

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Amyloidoses are a group of diseases caused by the structural disorder of proteins in which normally soluble proteins are deposited in tissues as insoluble amyloid fibrils made up of β-pleated sheets. Nucleation dependent polymerization or seeding is postulated as a model of fibril formation in several kinds of amyloidoses including peon diseases. Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of the disease have been reported in several types of amyloidoses, such as prion diseases, mouse AApoAII amyloidosis and mouse amyloid AA amyloidosis. Families with transthyretin (TTR)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR-amyloid depositing at an earlier age in successive generations. Notably, descendents of affected mothers appear to be more prone to anticipation than descendents of affected fathers. The molecular bases of anticipation in FAT have remained to be determined. We hypothesized that th … More e anticipation in FAP may be caused by transmission of TTR-amyloid fibrils from affected mothers to their offspring, and the purpose of this study was to examine this hypothesis.First, we investigated mammary gland tissues of three female patients with FAP who were proven to have amyloid deposition in abdominal fat tissues. There was a variable amount of amyloid deposition positively stained with Congo red, and the seventies of the amyloid deposition in mammary glands were almost proportional to the clinical seventies of the patients. Amyloid deposition was seen mainly in the epithelial portion of the mammary gland, surrounding the glandular epithelial cells that form the alveoli. Furthermore, in some alveoli, alveolar epithelial cells were detached so that deposited amyloid was directly adjacent to or projecting into the lumen of the alveoli. We consider that amyloid deposits in mammary glands, especially those that directly come in contact with milk in the glandular lumens, may be the source of amyloid fibrils that could be transmitted to breast-fed offspringSecondly, we asked if administration of TTR-amyloid fibrils (ATTR) extracted from an patient with FAP having variant TTR (Val30Met) would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP. The ATTR fibrils were isolated according to Pras and colleagues as water suspension fractions from an autopsied heart of a Japanese patient with FAP heterozygous with normal and Va130Met variant TTRs. The isolated amyloid fibrils were injected into the tail veins of 8-13-mounth-old transgenic mice. An equal volume of DW was injected into transgenic mice of the same age as controls. After 4 or 12 months, the transgenic mice were killed following anesthetization with ether. Various tissues were excised and subjected to pathological examinations. Twelve months after injection, congophilic amyloid deposits were observed in the various tissues (esophagus, stomach, intestine, lung, liver, kidney, heart) of all the 5 transgenic mice injected with TTR, whereas no deposits were detected in any of the five control transgenic littermates injected with DW. This results clearly showed that ATTR fibrils extracted from the heart of an FAP patient exerted amyloidosis-accelerating activity in vivo. In immunohistochemical analyses, the amyloid deposits in all the five ATTR-injected transgenic mice reacted only with anti-mouse AApoAII antibody, not with anti-human TTR antibody. These results indicated that administration of human ATTR fibrils did accelerate deposition of mouse AApoAII amyloid, and not the same human ATTR. Less