Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 microM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conform...

We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control pa...

Analytical ultracentrifugation methods were utilized to further characterize the acid denaturation pathways of wild-type, V30M, and L55P transthyretin (TTR) that generate intermediates leading to amyloid fibril formation and possibly the diseases senile systemic amyloidosis and familial amyloid polyneuropathy. Equilibrium and velocity methods were employed herein to characterize the TTR quatern...

In amyloidosis, normally innocuous soluble proteins polymerize to form insoluble fibrils. Amyloid fibril formation and deposition have been associated with a wide range of diseases, including spongiform encephalopathies, Alzheimer's disease, and familial amyloid polyneuropathies (FAP). In certain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homo...

The L55P transthyretin (TTR) familial amyloid polyneuropathy-associated variant is distinct from the other TTR variants studied to date and the wild-type protein in that the L55P tetramer can dissociate to the monomeric amyloidogenic intermediate and form fibril precursors under physiological conditions (pH 7.0, 37 degrees C). The activation barrier associated with L55P-TTR tetramer dissociatio...

Electroneurophysiological studies were performed in 15 patients with familial amyloid neuropathy (ages 29 to 67 years) and in 16 symptom-free members of affected families (ages 9 to 64 years). These studies included needle EMG, motor conduction velocities of deep peroneal and median nerves, sensory conduction velocities, sensory potentials, and nerve potentials of the sural and medium nerves. R...

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid deposition in the cerebral neuropil and vasculature. These amyloid deposits comprise predominantly fragments and full-length (40 or 42 residue) forms of the amyloid beta-protein (Abeta) organized into fibrillar assemblies. Compelling evidence indicates that factors that increase overall Abeta producti...

BACKGROUND Portuguese type familial amyloid polyneuropathy (FAP) is a neuropathic amyloidosis caused by a mutant transthyretin (TTR). Varying degrees of renal involvement have been reported. Our aim was to assess the value of microalbuminuria (MA) for predicting clinical neurological disease and overt nephropathy in TTR-related amyloidosis. METHODS All subjects had the TTR Val30Met mutation, ...

Background Transthyretin Familial Amyloid Polyneuropathy (TTRFAP) is a rare, progressive, debilitating and life-threatening neurodegenerative disease. TTR-FAP is a rare disease worldwide. In Europe a disease is defined as rare when it affects less than 1 in 2000 inhabitants. Portugal has the largest cluster worldwide nonetheless recent Portuguese epidemiologic data is lacking. The purpose of th...

Background Hereditary amyloidosis represents approximately 4% of the total cases of amyloidoses. The most frequent familial type is caused by deposition of mutated transthyretin (TTR, prealbumin). So far it has been identified more than 100 mutations in the transthyretin gene and type of causal mutation is also characterized by a clinical picture of the disease. The most common variant is a neu...