. Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2681-6. PubMed.


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  1. Transthyretin is an abundant blood protein that binds and transports thyroid hormones. It has been known for a number of years that transthyretin can also bind the β amyloid peptide (Aβ) associated with Alzheimer disease. Both in vitro studies and in vivo studies using the nematode worm C. elegans have shown that transthyretin can inhibit the aggregation of Aβ into insoluble amyloid fibers. This study by Buxbaum et al. uses transgenic mouse models to demonstrate that increased expression of transthyretin can protect transgenic mice from behavioral deficits caused by Aβ expression, and loss of transthyretin expression exacerbates these behavioral deficits. These studies support the idea that transthyretin might have a natural role as a chaperone protein for Aβ, serving to combat the aggregation of Aβ into amyloid or some other toxic form.

    Could manipulation of transthyretin expression in people help protect them from Alzheimer disease? This is a tricky question, because paradoxically transthyretin itself is associated with amyloid disease. Familial amyloid polyneuropathy, a fatal disease, is caused by mutations in transthyretin that cause the transthyretin protein itself to form amyloid. Normal (not mutated) transthyretin can also form amyloid deposits in the heart and brain, as is observed in cases of systemic senile amyloidosis. Interestingly, small heat shock proteins, classic chaperone proteins that can inhibit Aβ from forming amyloid, also form insoluble deposits by themselves under appropriate conditions. Perhaps proteins evolved to interact with aggregation-prone proteins become predisposed to aggregate themselves. These considerations suggest that manipulation of the expression transthyretin (or other putative Aβ chaperone proteins) might be therapeutic, but might require careful titration of the expression of these proteins. This study also raises the possibility that reduced expression of transthyretin might be a risk factor for developing Alzheimer disease.

  2. Transthyretin (TTR) is a blood and cerebrospinal fluid (CSF) carrier protein for thyroxine and retinol (in association with the retinol-binding protein). In the last few years an increasing number of reports have linked TTR to Alzheimer disease (AD). Specifically, TTR has been suggested as a neuroprotective factor for disease progression, given its ability to sequester and clear the amyloid-β peptide (Aβ) out of the brain.

    This article generally confirms the previous reports for a role of TTR in AD. The study shows that 1) in the absence of TTR there is increased amyloid load in the brain of APP transgenic mice; 2) overexpression of 90 copies of the human TTR gene in APP transgenic mice decreases amyloid load; 3) TTR overexpression in APP transgenic mice reverts the cognitive impairment normally observed in this animal model of AD. Of note, this study confirms a previous one (1) in which the absence of TTR was shown to accelerate the memory decline normally associated with age. This may be related to a TTR function that is ”independent of its interaction with Aβ,” as recognized by Buxbaum et al.

    This last observation points to a function of TTR in behavior that may be unrelated to its ability to sequester Aβ and prevent Aβ deposition. Therefore, the role of TTR in preventing Aβ deposition may not be connected to the cognitive performance improvement observed in APP transgenic mice overexpressing TTR.

    As for the role of TTR in preventing amyloid deposition, shown in at least two studies (this one and [2]), it is of relevance to discuss the origin of TTR within the brain. Within the brain, TTR expression is restricted to the choroid plexus (from where it is secreted towards the CSF) (2) and the meninges (4). It is therefore important to clarify whether the overexpression of TTR (90 copies of the gene) in mice originates the synthesis of the protein in other, “non-natural” sites of the brain parenchyma, which may be misleading in interpreting the role of TTR in AD.

    TTR, among other CSF proteins (cystatin C, apolipoprotein J, and insulin growth factor 1, [5-7]) is reported to be protective in AD, not only by sequestering Aβ from reaching concentrations that may promote deposition as amyloid, but also by facilitating Aβ clearance out of the brain through receptors located both in the choroid plexus (7) and in the endothelial cells of the blood-brain barrier (8). It is therefore reasonable to suggest that increasing the levels of these proteins might be a therapeutic approach in AD. However, this possibility raises main concerns, of which two should certainly be investigated carefully. First, all these proteins have well-described physiological functions, some of which relate to behavior. Increasing their concentrations may pose health risks higher than the potential benefit for AD. Second, it is necessary to further study whether and how these CSF proteins can successfully reach the major brain sites of amyloid deposition in AD.


    . Transthyretin influences spatial reference memory. Neurobiol Learn Mem. 2007 Oct;88(3):381-5. PubMed.

    . Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin). J Neurosci. 2007 Jun 27;27(26):7006-10. PubMed.

    . Transthyretin and Alzheimer's disease: where in the brain?. Neurobiol Aging. 2007 May;28(5):713-8. PubMed.

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  3. This paper shows that overexpression of wild-type human transthyretin (TTR) in APP transgenic mice ameliorates Aβ amyloid deposition and improves cognitive function. Targeted silencing of the mouse endogenous TTR gene accelerated the development of the neuropathologic phenotype, confirming recent reports of enhanced TTR expression in the brain of APP transgenic mice and enhanced Aβ amyloid deposition in these mice lacking TTR. Using in vitro techniques, a direct binding between TTR and Aβ is shown, extending previous in vitro studies by Alexander L. Scharzman and Dmitry Goldgaber that showed that binding of TTR to Aβ results in decreased amyloid formation.

    While the precise molecular nature of the transthyretin-binding species of Aβ was not defined, the data show that tetrameric TTR binds aggregated Aβ. The findings suggest that a physical interaction between TTR and Aβ prevents the toxicity and plaque formation by interfering with aggregation of Aβ species larger than monomers. While the endogenous protein most likely has an ongoing role in prevention of amyloid formation, its concentration may not be sufficient under pathological conditions that favor amyloid formation. It is suggested that increasing cerebral TTR synthesis is a potential therapeutic/prophylactic approach to human Alzheimer disease. However, induction of expression of the full-length protein may prove to have negative effects, especially because wild-type TTR can form amyloid fibrils. It is more likely that for therapeutic purposes, a biologically active peptidomimetic compound with the Aβ-binding properties of TTR can be designed.

    It is of special interest that potentially amyloidogenic proteins can bind to each other and inhibit amyloid fibril formation. Aβ has a high tendency to form amyloidogenic aggregations, and the formation of amyloid fibrils is inhibited by binding to the tetrameric form of wild-type TTR. Unlike TTR, only a Leu68Gln variant of cystatin C can form amyloid fibrils. However, both wild-type and variant cystatin C bind monomeric soluble Aβ and inhibit Aβ oligomerization and fibril formation. Future studies will show whether cerebral or systemic amyloidoses can be halted or prevented by modulation of expression of another amyloidogenic protein, or more likely by a drug that will be developed to mimic the function of such a protein.

  4. Transthyretin (TTR) interaction with Aβ in the CSF has been known at least since 1994 when Schwarzman and colleagues (Schwarzman et al., 1994) concluded that TTR was the major Aβ binding protein in the CSF, observing a decrease in the aggregation state of the peptide. Two years later, the same group confirmed the inhibitory effect of TTR on Aβ formation and consequent reduction in its toxicity (Schwarzman et al., 1996). Later on, the same group of researchers performed in vitro studies using different TTR mutations and concluded on the differential binding (i.e., physical interaction) and inhibition of Aβ aggregation by those variants to (Schwarzman et al., 2004). At this point, the characterization of the interaction between the two molecules was missing.

    The work by Buxbaum and coworkers further explores the protective role of TTR using animal models, but does not unravel mechanisms behind the observed protection; details on the physical interaction between the two molecules are still missing.

    A recent report by Costa et al., FEBS Letters, provides a Kd for the WT TTR and soluble Aβ interaction, and goes further, showing that TTR also binds to oligomeric and fibrillar Aβ with similar affinities; most interestingly, it is demonstrated that besides inhibiting Aβ aggregation, TTR is able to disaggregate the peptide fibrils in vitro, opening new perspectives on the role of TTR in Aβ deposition. Regarding TTR variants, the intensity of binding inversely correlates with the amyloidogenic potential (TTR T119M > WT > V30M > Y78F > L55P), immediately drawing attention to TTR protein stability and Aβ binding. The mechanism underlying TTR protection in Aβ toxicity is largely unknown.


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