Resveratrol Administration Increases Transthyretin Protein Levels, Ameliorating AD Features: The Importance of Transthyretin Tetrameric Stability

• Main Authors: Luís Miguel Santos (Author), Daniela Rodrigues (Author), Mobina Alemi (Author), Sara Costa Silva (Author), Carlos Alexandre Ribeiro (Author), Isabel Cardoso (Author)
• Formato: Livro
• Publicado em: BMC, 2016-06-01T00:00:00Z.
• Assuntos: article
• Acesso em linha: Connect to this object online.

Resumo

Abstract Previous in vivo work showed that resveratrol has beneficial effects in Alzheimer's disease (AD) pathology, resulting in increased expression of transthyretin (TTR). TTR binds amyloid-beta (Aβ) peptide, avoiding its aggregation and toxicity, and is reduced in the cerebrospinal fluid (CSF) and plasma in AD. Further, resveratrol binds TTR, stabilizing the native TTR tetrameric structure. To further explore the mechanism of neuroprotection conferred by TTR in AD, resveratrol was administered in the diet to 5- to 8-month-old AD transgenic female mice carrying just 1 copy of the mouse TTR gene for 2 months. Effects in brain Aβ burden were evaluated by immunohistochemistry, and total brain Aβ levels by ELISA, showing a striking decrease in both parameters in treated animals. In addition, total brain lipoprotein-related receptor protein 1 (LRP1) levels were increased in treated animals, although its gene expression was unaltered. To further understand the mechanism(s) underlying such improvement in AD features, we measured TTR plasma levels, showing that TTR increased in resveratrol-treated mice, whereas liver TTR gene transcription was not altered. These results strengthen the stability hypothesis, which postulates that TTR is unstable in AD, leading to accelerated clearance and lower levels. Therefore, resveratrol, which stabilizes the TTR tetramer results in TTR-normalized clearance, increases the protein plasma levels. In turn, stabilized TTR binds more strongly to Aβ peptide, avoiding its aggregation. Our results represent a step forward in the understanding of the mechanism underlying TTR protection in AD and highlight the possibility of using TTR stabilization as a therapeutic target in AD.

Descrição do item

10.2119/molmed.2016.00124
1076-1551
1528-3658