Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, is a brain disorder affecting the elderly and it is one of the causes of human disability and death in the developed world [1]
TTR has been suggested as an amyloid beta peptide (A-Beta) carrier [8,9,10,18] and attempts to relate TTR levels and Alzheimer’s disease have been made [30,31]
Proteolytic activity has been attributed to TTR as a novel physiological function [16]
Summary
Alzheimer’s disease (AD), the most common form of dementia, is a brain disorder affecting the elderly and it is one of the causes of human disability and death in the developed world [1] This disorder is characterized by intracellular neurofibrillary tangles, resulting from the accumulation of hyperphosphorylated microtubule-associated tau, as well as extracellular amyloid deposits called neuritic or senile plaques [2]; both lesions occur in the central nervous system, in the hippocampus and the cortex. These plaques are primarily composed of a peptide with 40– 42/43 amino acids, amyloid beta peptide (A-Beta) which is formed through the sequential cleavage of the amyloid precursor protein (APP) by beta and gamma-secretases [3]. Over 100 TTR mutations have been associated with TTR related amyloid deposition in Familial Amyloidotic Polyneuropathy, affecting the peripheral nervous system
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