Joana Almeida Palha

Transthyretin is involved in depression-like behaviour and exploratory activity

Transthyretin (TTR), the major transporter of thyroid hormones and vitamin A in cerebrospinal fluid (CSF), binds the Alzheimer β‐peptide and thus might confer protection against neurodegeneration. In addition, altered TTR levels have been described in the CSF of patients with psychiatric disorders, yet its function in the CNS is far from understood. To determine the role of TTR in behaviour we evaluated the performance of TTR‐null mice in standardized tasks described to assess depression, exploratory activity and anxiety. We show that the absence of TTR is associated with increased exploratory activity and reduced signs of depressive‐like behaviour. In order to investigate the mechanism underlying these alterations, we measured the levels of cathecolamines. We found that the levels of noradrenaline were significantly increased in the limbic forebrain of TTR‐null mice. This report represents the first clear indication that TTR plays a role in behaviour, probably by modulation of the noradrenergic system.

Transthyretin and Alzheimer's disease: where in the brain?

Transthyretin (TTR), a carrier protein for thyroxine and retinol in plasma and cerebrospinal fluid (CSF), has been shown to bind the amyloid beta peptide. Accordingly, TTR has been suggested to protect against amyloid beta deposition, a key pathological feature in Alzheimers disease (AD). Supporting this view are the reduced TTR levels found in CSF of patients with AD, as well as reports of altered TTR expression in the cortex and hippocampus of AD rodent models. Importantly, early characterization of TTR distribution revealed the choroid plexus as the site of TTR synthesis within the brain. To resolve this controversy we used precise laser microdissection technology to assay for TTR mRNA expression. Our results clearly demonstrate that TTR is not produced in the brain parenchyma of wild-type mice nor in two different transgenic mouse models of AD, suggesting that contamination by choroid plexus contributed to the recent results indicating TTR production in various brain regions. The relevance of TTR to AD should now take into consideration TTR production by the choroid plexus and its ability, in the CSF, to sequester the amyloid beta peptide.

The choroid plexus response to peripheral inflammatory stimulus

Increased interest is being raised on the interaction between systemic inflammation and the brain. The choroid plexus (CP) constitutes a monolayer of epithelial cells located within the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF). Despite the knowledge that the CP capillaries are fenestrated, allowing free passage of molecules and cells, the involvement of the vast blood-brain boundary represented by the CP/CSF barrier in brain inflammatory processes has seldom been considered. In the present study we investigate, in mice, how the expression of genes encoding major constitutively expressed CP proteins is influenced by a systemic inflammatory stimulus. Confirming that the CP responds to peripheral inflammation, the messenger RNA (mRNA) levels of the pro-inflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha are rapidly induced. As for the constitutively expressed proteins, while the mRNA for genes encoding transthyretin and transferrin remain unaltered by the inflammatory challenge, that for prostaglandin D2 synthase (LPTGDS) is up-regulated at 6 h, and stays up-regulated up to 24 h after lipopolysacharide administration. Accordingly, LPTGDS CSF levels are also augmented. LPTGDS catalyzes the synthesis of the major prostanoid of the CNS and, being increased in the CSF, might mediate immune signaling into the brain. These observations emphasize that the CP must be considered a relevant mediator of immune signals between the periphery and the brain.

Structure of the Val122Ile variant transthyretin - a cardiomyopathic mutant.

The Val122Ile mutant transthyretin (TTR Ile122) is an amyloidogenic protein which has been described as the major protein component of amyloid fibrils isolated from patients with familial amyloidotic cardiomyopathy (FAC), a disease characterized by cardiac failure and amyloid deposits in the heart. The reasons for the deposition of TTR are still unknown and it is conceivable that a conformational alteration, resulting from the mutation, is fundamental for amyloid formation. The three-dimensional structure of TTR Ile122 was determined and refined to a crystallographic R factor of 15.8% at 1.9 A resolution. The r.m.s. deviation from ideality in bond distances is 0.019 A and in angle-bonded distances is 0.027 A. The presence of two crystallographically independent monomers in the asymmetric unit allowed additional means of estimation of atomic coordinate error. The structure of the mutant is essentially identical to that of the wild-type transthyretin (TTR). The largest deviations occur in surface loops and in the region of the substitution. The protein is a tetramer composed of identical subunits; each monomer has two four-stranded beta-sheets which are extended to eight-stranded beta-sheets when two monomers associate through hydrogen bonds forming a dimer, which is the crystallographic asymmetric unit. The replacement of valine for isoleucine introduces very small alterations in relation to the wild-type protein; nevertheless they seem to confirm a tendency for a less stable tetrameric structure. This would support the idea that the tetrameric structure might be disrupted in amyloid fibrils.

NR4A2 and schizophrenia: Lack of association in a Portuguese/Brazilian study

The present study investigates the association of mutations in the nuclear receptor NR4A2 in schizophrenic patients. The human Nur‐related receptor 1, NR4A2, is an orphan nuclear receptor that can be constitutively active as a transcription factor and for which no natural ligand has yet been identified. Alone or with retinoid X receptor, RXR, NR4A2 influences the expression of several genes important for human brain development and regulation. In the absence of Nurr1 (the mouse homologue to human NR4A2), ventral mesencephalic dopaminergic mouse neurons evidence severe developmental failure, a condition that is lethal soon after birth. Nurr1 involvement in the dopaminergic system makes it a good candidate for study in neuropsychiatric disorders such as schizophrenia and Parkinson disease. Evidence by others support this hypothesis (1) mapping of the NR4A2 gene to chromosome 2q22‐23, a region with suggestive linkage to schizophrenia and (2) identification of mutations in patients with schizophrenia (c.366‐369delTAC, c.308A > G, c.‐469delG), manic depression (c.289A > G), and familial Parkinsons disease (c.‐291delT, c.‐245T > G). To further extend these observations, we searched for all these mutations in 176 Caucasian Portuguese and 82 Caucasian Brazilian subjects with lifetime diagnosis of schizophrenia. The study failed to identify any of the described mutations in patients or controls. Nevertheless, these negative results do not exclude altered expression of nuclear receptors in schizophrenia or the presence of other mutations.