Article

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

Division of Rheumatology Research, W. M. Keck Autoimmune Disease Center, and Department of Molecular and Experimental Medicine, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2008; 105(7):2681-6. DOI: 10.1073/pnas.0712197105
Source: PubMed

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.

0 Followers
 · 
101 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular simulations are now commonly used to complement experimental techniques in investigating amyloids and their role in human diseases. In this chapter, we will summarize techniques and approaches often used in amyloid simulations and will present recent success stories. Our examples will be focused on lessons learned from molecular dynamics simulations in aqueous environments that start from preformed aggregates. These studies explore the limitations that arise from the choice of force field, the role of mutations in the growth of amyloid aggregates, segmental polymorphism, and the importance of cross-seeding. Furthermore, they give evidence for potential toxicity mechanisms. We finally discuss the role of molecular simulations in the search for aggregation inhibitors
    Advances in Protein Chemistry and Structural Biology, Edited by Tatyana Karabencheva-Christova, 09/2014: chapter CHAPTER FOUR: pages 113-141; Academic Press.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.
    Journal of Alzheimer's disease: JAD 10/2013; 39(2). DOI:10.3233/JAD-131355 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-β (Aβ) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with Aβ lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble Aβ(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small Aβ(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic Aβ(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble Aβ(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2012; 32(23):7852-61. DOI:10.1523/JNEUROSCI.5901-11.2012 · 6.75 Impact Factor

Preview

Download
2 Downloads
Available from