Transthyretin Anti-Amyloidogenic and Fibril Disrupting Activities of Bacopa monnieri (L.) Wettst (Brahmi) Extract.

Fredrick Nwude Eze,Porntip Prapunpoj,Kornkanok Ingkaninan

doi:10.3390/biom9120845

Fredrick Nwude Eze, Porntip Prapunpoj + Show 1 more

Open Access

https://doi.org/10.3390/biom9120845

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Journal: Biomolecules	Publication Date: Dec 9, 2019
Citations: 6	License type: CC BY 4.0

Affiliation: Prince of Songkla University, Naresuan University

Abstract

The homotetrameric plasma protein transthyretin (TTR), is responsible for a series of debilitating and often fatal disorders in humans known as transthyretin amyloidosis. Currently, there is no cure for TTR amyloidosis and treatment options are rare. Thus, the identification and development of effective and safe therapeutic agents remain a research imperative. The objective of this study was to determine the effectiveness of Bacopa monnieri extract (BME) in the modulation of TTR amyloidogenesis and disruption of preformed fibrils. Using aggregation assays and transmission electron microscopy, it was found that BME abrogated the formation of human TTR aggregates and mature fibrils but did not dis-aggregate pre-formed fibrils. Through acid-mediated and urea-mediated denaturation assays, it was revealed that BME mitigated the dissociation of folded human TTR and L55P TTR into monomers. ANS binding and glutaraldehyde cross-linking assays showed that BME binds at the thyroxine-binding site and possibly enhanced the quaternary structural stability of native TTR. Together, our results suggest that BME bioactives prevented the formation of TTR fibrils by attenuating the disassembly of tetramers into monomers. These findings open up the possibility of further exploration of BME as a potential resource of valuable anti-TTR amyloidosis therapeutic ingredients.

Highlights

Transthyretin (TTR) is one of the most abundant plasma proteins and is involved in the transport of thyroxine and vitamin A [1,2]
TTR in its pathological form, amyloid transthyretin (ATTR), is responsible for a spectrum of progressive, debilitating, life-altering neurodegenerative diseases known as ATTR amyloidosis which originated from the misfolding, mis-aggregation and systemic deposition of ATTR in several organs
Amyloidogenesis and fibril formation by TTR is closely associated with the development of the devastating clinical features that characterize ATTR amyloidosis

Summary

Introduction

Transthyretin (TTR) is one of the most abundant plasma proteins and is involved in the transport of thyroxine and vitamin A [1,2]. This 55 kDa homotetrameric protein synthesized in the choroid plexus is the main transporter of thyroxine (T4). Recent evidence seems to suggest a neuroprotective role of TTR in Alzheimer’s disease. TTR in its pathological form, amyloid transthyretin (ATTR), is responsible for a spectrum of progressive, debilitating, life-altering neurodegenerative diseases known as ATTR amyloidosis which originated from the misfolding, mis-aggregation and systemic deposition of ATTR in several organs. At the moment there is no cure for the disease and effective therapeutic interventions are very limited. There is a pressing need for investigations targeted toward the identification or development of safe and effective therapeutic interventions

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