Transthyretin is one of a handful of proteins that, like amyloid-β, can adopt a β-sheet conformation and aggregate as amyloid. So it may seem counterintuitive that transthyretin could be used to prevent Aβ toxicity, yet that is exactly the proposition of a paper in this week’s PNAS online. Researchers led by Joel Buxbaum at The Scripps Research Institute, La Jolla, California, report that transthyretin (TTR) protects against Aβ pathology in mice. They suggest that TTR works like a chaperone and hint that this activity might lead to new therapeutic approaches to treating Alzheimer disease.

Transthyretin is a serum and cerebrospinal fluid (CSF) carrier that binds thyroid hormones and other small molecules. It also binds to Aβ in the CSF (see Schwarzman et al., 1994), is found adjacent to Aβ plaques in transgenic mice, and prevents Aβ aggregation in C. elegans (see Link, 1995). In addition, Aβ deposition speeds up when one copy of TTR is deleted in APP/presenilin double transgenic (APPSwe/PS1δE9) mice (see Choi et al., 2007), so the idea that transthyretin may be protective in AD is not new. Now, Buxbaum and colleagues show that overexpressing TTR is also protective in mice and that TTR physically binds to Aβ, which supports the notion that “increasing cerebral TTR synthesis is a potential therapeutic/prophylactic approach to human AD,” as the authors suggest.

Buxbaum and colleagues evaluated the offspring of APP23 transgenic mice (expressing human APP carrying the Swedish mutation) crossed with animals overexpressing human TTR. They also evaluated what happens when TTR is missing by testing APP23 mice generated in a mouse TTR-negative background. The investigators found that overexpressing human TTR protects mice against cognitive and spatial deficits. In the Barnes maze test, 15-month-old APP23 animals had more errors and fared more poorly in finding the escape hole than did wild-type animals. APP23 mice overexpressing human TTR performed about as well as wild-type controls, indicating a protective effect of transthyretin. Lack of endogenous mouse TTR had the opposite effect. Younger (5.5 months old) APP23 mice performed about as well as controls, but in the absence of mouse TTR the animals made significant errors.

Immunohistochemical analysis indicates that these behavioral changes are related to Aβ pathology. While APP23 animals normally have Aβ deposits by 16 months, three out of 24 APP23/hTTR animals had no detectable deposits by that age, and in those that had detectable deposits, they were significantly fewer (around half), and soluble Aβ levels were also about half compared to control APP23 animals. In contrast, the researchers found detectable Aβ deposits in seven of 11 5.5-month-old APP23 mice lacking endogenous TTR—Aβ deposits are normally very rare in mice at that age. The amount of formic acid-soluble Aβ was nearly doubled in the mTTR-negative mice as well.

Correlating Aβ levels and deposits with TTR does mean the two proteins react physically, but the researchers showed, using surface plasmon resonance, that TTR interacts with Aβ monomers (both Aβ40 and Aβ42) and fibrils. Interestingly, mouse TTR had much higher affinity for any Aβ form than did human TTR.

All told, the findings indicate that TTR can ameliorate the pathology and behavioral symptoms associated with Aβ overproduction in a mammalian model. “It appears that the interaction is physical and that TTR may behave in a chaperone-like manner for molecular species of Aβ larger than monomers. The observations support the novel notion that increasing cerebral TTR synthesis is a potential therapeutic/prophylactic approach to human AD,” write the authors.—Tom Fagan


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  1. 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.


    . Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8368-72. PubMed.

    . Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation. Ciba Found Symp. 1996;199:146-60; discussion 160-4. PubMed.

    . Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants. Amyloid. 2004 Mar;11(1):1-9. PubMed.

    . Transthyretin binding to A-Beta peptide--impact on A-Beta fibrillogenesis and toxicity. FEBS Lett. 2008 Mar 19;582(6):936-42. PubMed.

  2. 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.

    View all comments by Chris Link
  3. 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.

    . Transthyretin expression in the rat brain: effect of thyroid functional state and role in thyroxine transport. Brain Res. 1993 Dec 31;632(1-2):114-20. PubMed.

    . Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat Genet. 2007 Dec;39(12):1440-2. PubMed.

    . Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007 May;27(5):909-18. PubMed.

    . Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J Neurosci. 2005 Nov 23;25(47):10884-93. PubMed.

    . Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2007 Apr;4(2):191-7. PubMed.

    View all comments by Joao Sousa
  4. 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.

    View all comments by Efrat Levy


Paper Citations

  1. . Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8368-72. PubMed.
  2. . Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1995 Sep;92(20):9368-72.
  3. . Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin). J Neurosci. 2007 Jun 27;27(26):7006-10. PubMed.

Further Reading

Primary Papers

  1. . 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.