Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Joel N. Buxbaum, Zhengyi Ye, Natàlia Reixach, Linsey Friske, Coree Levy, Pritam Das, Todd Golde, Eliezer Masliah, Amanda R. Roberts, Tamas Bartfai

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (Aβ1-42) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with Aβ in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and Aβ aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic Aβ aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.

Original languageEnglish (US)
Pages (from-to)2681-2686
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number7
DOIs
StatePublished - Feb 19 2008

Keywords

  • Amyloidosis
  • Dementia
  • Protein interaction
  • Protein misfolding

ASJC Scopus subject areas

  • General

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    Buxbaum, J. N., Ye, Z., Reixach, N., Friske, L., Levy, C., Das, P., Golde, T., Masliah, E., Roberts, A. R., & Bartfai, T. (2008). Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity. Proceedings of the National Academy of Sciences of the United States of America, 105(7), 2681-2686. https://doi.org/10.1073/pnas.0712197105