Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of A 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: 9.67). 03/2008; 105(7):2681-6. DOI: 10.1073/pnas.0712197105
Source: PubMed


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.

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    • "Another group of sequester proteins, such as apolipoproteins (apolipoprotein E [apoE], apolipoprotein A1 [apoA1], and apolipoprotein J [apoJ]), bind to Ab to prevent its aggregation and reduce its toxicity and are involved in Ab clearance [12] [13] [14]. Transthyretin (TTR) or pre-albumin has been found in cerebrospinal fluid (CSF) as an Ab-binding protein and suppresses the toxicity of oligomers [15] [16]. Thus, these sequester proteins have neuroprotective functions and may help delay the pathologic progression of AD via Ab clearance. "
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    ABSTRACT: Introduction: There are no blood-based biomarkers for cognitive decline in aging, or mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cumulative evidence suggests that apolipoproteins, complement system, and transthyretin are involved in AD pathogenesis by sequestration of amyloid β. However, there is no clinical study to assess the utility of "sequester proteins" in risk assessment and/or diagnosis of MCI and AD. Methods: Serum levels of sequester proteins and their clinical potential in cognitive decline assessment were analyzed by longitudinal and cross-sectional studies using independent cohorts and were confirmed by a prospective study. Results: A combination of apolipoprotein A1, complement C3, and transthyretin achieved an area under the curve of 0.89 (sensitivity 91% and specificity 80%) in MCI versus healthy controls and also discriminated individuals with mild cognitive decline from healthy controls. Discussion: A set of sequester proteins could be blood-based biomarkers for assessment of early stages of cognitive decline.
    Preview · Article · Jun 2015
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    • "Recent studies of amyloid growth indicate that, in addition to pathogenic self-association, cross seeding plays a critical role in amyloid diseases. Examples are the Aβ–tau, Aβ–amylin, the Aβ–α-synuclein, the Aβ–transthyretin, and the amylin–insulin interactions (Andreetto et al., 2010; Buxbaum et al., 2008; Giasson et al., 2003; Guo, Arai, Miklossy, & McGeer, 2006; Nicolls, 2004). "
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    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
    Full-text · Chapter · Sep 2014
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    • "However, other changes were seen in the transcriptome of these mice that could be a consequence of an overabundance of FMR1 mRNA. Interestingly, the two most altered genes in the transcriptome were transthyretin (Trt), and serpina3, putative biomarkers for Alzheimer’s disease [84,85]. Serpina3, a serine protease inhibitor that is released during inflammatory responses, was up-regulated and may reflect the increased prevalence of autoimmune disease (for example, lupus, multiple sclerosis, fibromyalgia, thyroid disease) in females with the FMR1 premutation [86]. "
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    ABSTRACT: Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.
    Full-text · Article · Jul 2014 · Journal of Neurodevelopmental Disorders
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