Transthyretin-related familial amyloidotic
polyneuropathy is a systemic
amyloidosis caused by mutations in the
transthyretin gene. Extracellular deposition of
amyloid is the common pathologic hallmark of
amyloidoses including
Alzheimer disease,
AL amyloidosis,
AA amyloidosis, and familial amyloidotic
polyneuropathy. However, the exact relationship between
amyloid deposition and cell death has not yet been clarified. To elucidate this relationship, we studied the effect of
transthyretin amyloid fibrils and prefibrillar aggregates on cells by using autopsy tissues obtained from 8 patients with familial amyloidotic
polyneuropathy, as well as cultured cell lines. Ultrastructural studies of
amyloid-laden cardiomyocytes showed that intracellular structural changes correlated with the degree of
amyloid deposition and may reflect metabolic disturbances caused by physical limitations imposed by the
amyloid deposits.
Amyloid-laden vascular endothelial cells, mesangial cells, smooth muscle cells, Schwann cells, and cardiomyocytes, however, had well-preserved cell nuclei and showed no apoptotic changes, even when cells were completely surrounded by prefibrillar
transthyretin aggregates and
amyloid fibrils. Synthesized prefibrillar
transthyretin aggregates,
transthyretin fibrils, and
amyloid fibrils obtained from patients with familial amyloidotic
polyneuropathy evidenced no cytotoxicity in cell culture experiments. Our data thus indicate that neither
transthyretin amyloid fibrils nor prefibrillar
transthyretin aggregates directly induced apoptosis. However, cellular metabolic disturbances caused by cells' being physically confined by
amyloid deposits may induce cell degeneration.