Modulating Role of TTR in Aβ Toxicity, from Health to Disease

Abstract

Amyloidosis is a generic term that refers to a wide spectrum of diseases that are characterized by the deposition of proteins in different organs, forming insoluble aggregates. Examples include islet amyloid polypeptide (IAPP) associated with diabetes type 2, prion protein (PrP) related with spongiform encephalopathies, (TTR) associated with familial amyloidotic polyneuropathy (FAP), and amyloid-beta (Aβ) peptide linked to Alzheimer's disease (AD), the most common form of dementia. Aβ peptide, thought to be the causative agent in AD, is generated upon sequential cleavage of the amyloid precursor protein (APP), by beta-and gamma-secretases, and it is believed that an imbalance between Aβ production and clearance results in its accumulation in the brain. TTR is a 55 kDa homotetrameric protein synthesized by the liver and choroid plexus of the brain and is involved in the transport of thyroid hormones and retinol. TTR protects against Aβ toxicity by binding the peptide, thus inhibiting its aggregation. Also, increased Aβ levels are found in both brain and plasma of AD mice with only one copy of the TTR gene, when compared to animals with two copies of the gene, suggesting a role for TTR in Aβ clearance. Growing evidence also suggests a wider role for TTR in central nervous system neuroprotection, including in the cases of ischemia, regeneration, and memory.