Transthyretin is involved in depression‐like behaviour and exploratory activity

Sousa, João Carlos; Grandela, Catarina; Fernández‐Ruiz, Javier; Miguel, Rosario de; Sousa, Liliana de; Magalhães, Ana; Saraiva, Maria João; Sousa, Nuno; Palha, Joana Almeida

doi:10.1046/j.1471-4159.2003.02309.x

Cited by 113 publications

(81 citation statements)

References 39 publications

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“…A behavioral, presumably neuronal function for TTR was proposed on the basis of studies of TTR knockouts that showed ''reduced signs of depressive activity and increased exploratory activity'' (24). Our data with respect to activity levels in the animals are consistent with those findings.…”

Section: Discussionsupporting

confidence: 88%

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

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

264

251

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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 (A␤ 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 A␤ in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and A␤ aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic A␤ 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.protein interaction ͉ protein misfolding ͉ amyloidosis ͉ dementia A relationship between Alzheimer's disease (AD) and transthyretin (TTR) has been hypothesized on the basis of reports of physical interaction between amyloidogenic (A␤) peptides and TTR proteins in vitro, prevention of A␤ aggregation in Caenorhabditis elegans transgenic for both mutant A␤ and TTR, increased cerebral transcription of the TTR gene in murine AD models, immunohistochemically detectable TTR in the vicinity of A␤ plaques in A␤ transgenic mice, and more aggressive histologic disease in such mice after local treatment with anti-TTR antibody (1-5). However, none of those studies demonstrated functional effects of the putative TTR-A␤ interaction. We performed genetic experiments designed to determine whether TTR has an effect on the development of the neuropathologic and behavioral phenotypes in a well characterized murine model of human AD. ResultsAPP23 mice, carrying the Swedish autosomal dominant AD mutation and displaying the neuropathologic (Congophilic plaques, gliosis, neuronal death, Congophilic angiopathy) and behavioral (defined cognitive deficits) features associated with human AD, were mated with mice overexpressing WT human TTR (hTTR) and animals in which both copies of the endogenous TTR gene had been silenced by targete...

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Section: Discussionsupporting

confidence: 88%

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

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

264

251

View full text Add to dashboard Cite

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“…and S.S.S., personal observations). In addition, the limbic forebrain of TTR-deficient mice exhibits significantly elevated levels of noradrenaline (Sousa et al, 2004), a catecholamine neurotransmitter that has been shown to modulate A␤ burden in a transgenic mouse model of AD (Kalinin et al, 2007). Finally, because retinol and thyroid hormones are essential for normal mammalian brain physiology and are particularly critical during development (Porterfield and Hendrich, 1993) and because TTR is the only thyroid hormone-binding protein found at a substantial level in the CSF (Herbert et al, 1986), it is possible that TTR reduction could cause developmental abnormalities.…”

Section: Increased Levels Of Cerebral A␤ Levels In Brains Of Hemizygomentioning

confidence: 99%

Accelerated A Deposition in APPswe/PS1 E9 Mice with Hemizygous Deletions of TTR (Transthyretin)

Choi

Leight

Lee

et al. 2007

Journal of Neuroscience

123

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A cardinal pathological lesion of Alzheimer's disease (AD) is the deposition of amyloid ␤ (A␤) in the brain. We previously reported that exposing transgenic mice harboring APPswe/PS1⌬E9 transgenes to an enriched environment resulted in reduced levels of A␤ peptides and deposition, findings that were correlated with an increase in the expression of TTR, encoding transthyretin (TTR). TTR is expressed at high levels in the choroid plexus and known to bind A␤ peptides and modulate their aggregation in vitro and in vivo. To explore the impact of TTR expression on A␤ levels and deposition in vivo, we crossed ceAPPswe/PS1⌬E9 transgenic mice to mice with genetic ablations of TTR. We now report that the levels of detergent-soluble and formic acid-soluble levels of A␤ and deposition are elevated in the brains of ceAPPswe/PS1⌬E9/TTR؉/؊ mice compared with age-matched ceAPPswe/PS1⌬E9/TTR؉/؉ mice. Moreover, A␤ deposition is significantly accelerated in the hippocampus and cortex of ceAPPswe/PS1⌬E9/TTR؉/؊ mice. Our results strongly suggest that TTR plays a critical role in modulating A␤ deposition in vivo.

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“…The products of these sequences have a variety of functions ranging from transcription factors to ion channels to a hormone transport factor. Interestingly, at least two of the factors, TTR (Stork et al 2001;Sousa et al 2004;Stein et al 2004) and NPAS2 (Garcia et al 2000), have been implicated in learning and memory.…”

Section: Learning and Memorymentioning

confidence: 99%

Reduced extinction of hippocampal-dependent memories in CPEB knockout mice

Berger-Sweeney¹,

Zearfoss²,

Richter³

2006

Learn. Mem.

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CPEB is a sequence-specific RNA binding protein that regulates translation at synapses. In neurons of CPEB knockout mice, synaptic efficacy is reduced. Here, we have performed a battery of behavioral tests and find that relative to wild-type animals, CPEB knockout mice, although similar on many baseline behaviors, have reduced extinction of memories on two hippocampal-dependent tasks. A corresponding microarray analysis reveals that about 0.14% of hippocampal genes have an altered expression in the CPEB knockout mouse. These data suggest that CPEB-dependent local protein synthesis may be an important cellular mechanism underlying extinction of hippocampal-dependent memories.The modulation of synaptic strength, which underlies long-term memory storage (Hering and Sheng 2001), may involve "synaptic tagging," where a stimulated synapse is tagged with a molecular mark that a neuron uses to distinguish naive from stimulated synapses (Martin et al. 2000). Based on the recognition of this tag, a neuron can modify the strength of its synaptic response upon subsequent stimulation. While the nature of the tag is unknown, protein synthesis is involved in its establishment or recognition (Kang and Schuman 1996;Huber et al. 2000;Scheetz et al. 2000;Richter and Lorenz 2002). One process that regulates translation at synapses is cytoplasmic polyadenylation; here, mRNAs have short poly(A) tails, but in response to activity, the poly(A) tails lengthen and translation ensues (Wu et al. 1998;Huang et al. 2002;Du and Richter 2005). CPEB is the factor responsible for polyadenylation; it is a sequence-specific RNA binding protein that once phosphorylated, activates a series of events that culminates in polyadenylation and translation (Mendez et al. 2000;Barnard et al. 2004;Sarkissian et al. 2004).In neurons, N-methyl-D-aspartate receptor (NMDAR) signaling mediates CPEB phosphorylation and resulting polyadenylation (Wu et al. 1998;Huang et al. 2002;Shin et al. 2004;Du and Richter 2005). The importance of CPEB is underscored by experiments showing that knockout (KO) mice have a deficit in longterm potentiation (LTP) in Schaffer collateral CA-1 hippocampal neurons stimulated with a theta-burst protocol (Alarcon et al. 2004). Here, we have examined the behavior of CPEB-knockout mice. The animals have normal motor and sensory function but exhibit alterations in reversal learning of a spatial navigation task, as well as reduced extinction in hippocampal-dependent memory tasks. In the hippocampus, CPEB regulates the expression of about 0.14% of genes. These data show that CPEB modifies not only gene expression and synaptic plasticity, but learning and memory as well.The generation of CPEB knockout (KO) mice has been described (Tay and Richter 2001). Physical evaluation and behavioral testing on 3-4-mo-old C57Bl/6 males (10 WT and 10 KO) included visual observation, weighing, forepaw grip strength (grip strength apparatus, San Diego Instruments) (Frick et al. 2000), rotorod motor coordination (San Diego Instruments), 12 h dark cycle locomoto...

show abstract

Transthyretin is involved in depression‐like behaviour and exploratory activity

Cited by 113 publications

References 39 publications

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

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

Accelerated A Deposition in APPswe/PS1 E9 Mice with Hemizygous Deletions of TTR (Transthyretin)

Reduced extinction of hippocampal-dependent memories in CPEB knockout mice

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