Abstract
Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer’s disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.
Highlights
Transthyretin (TTR), formerly called prealbumin as it migrates just in front of the albumin band, in electrophoresis, is a plasma protein secreted mainly by the liver and choroid plexus [1]
TTR is the key protein in familial amyloid polyneuropathy (FAP), a systemic amyloidosis characterized by the deposition of amyloid derived from mutated TTR, with a special involvement of the peripheral nervous system and firstly identified and described by the Portuguese neurologist Corino de Andrade [4]
Clearance of Aβ from the brain occurs via active transport at the blood–brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), in a process that is partially mediated by the low density lipoprotein receptor-related protein 1 (LRP1) [42], in addition to the removal of the peptide by several enzymes, mechanisms that are impaired in Alzheimer’s disease (AD)
Summary
Transthyretin (TTR), formerly called prealbumin as it migrates just in front of the albumin band, in electrophoresis, is a plasma protein secreted mainly by the liver and choroid plexus [1]. TTR is the key protein in familial amyloid polyneuropathy (FAP), a systemic amyloidosis characterized by the deposition of amyloid derived from mutated TTR, with a special involvement of the peripheral nervous system and firstly identified and described by the Portuguese neurologist Corino de Andrade [4]. Amyloidosis refers to a group of protein aggregation diseases, characterized by the extracellular deposition of those proteins in different organs, forming insoluble aggregates called amyloids [5]. TTR is acknowledged for its neuroprotective role in the central nervous system (CNS), such as in Alzheimer’s disease (AD), a form of localized amyloidosis affecting the brain, and the most common form of dementia. TTR involvement in neuroprotection is part of very recent knowledge, not fully established and constantly evolving.
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