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

Academic Article
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Overview

authors

  • Buxbaum, Joel
  • Ye, Z.
  • Reixach, Natalia
  • Friske, L.
  • Levy, C.
  • Das, P.
  • Golde, T.
  • Masliah, E.
  • Roberts, Amanda
  • Bartfai, Tamas

publication date

  • February 2008

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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 (Abeta(1-42)) 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 Abeta in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and Abeta aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic Abeta 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.

subject areas

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Animals
  • Behavior, Animal
  • Biochemical Phenomena
  • Biochemistry
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Prealbumin
  • Receptors, Albumin
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Research

keywords

  • amyloidosis
  • dementia
  • protein interaction
  • protein misfolding
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Identity

PubMed Central ID

  • PMC2268196

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0712197105

PubMed ID

  • 18272491
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Additional Document Info

start page

  • 2681

end page

  • 2686

volume

  • 105

issue

  • 7

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