The European Prevention of Alzheimer's Dementia Programme: An Innovative Medicines Initiative-funded partnership to facilitate secondary prevention of Alzheimer's disease dementia

INTRODUCTION: Tens of millions of people worldwide will develop Alzheimer's disease (AD), and only by intervening early in the preclinical disease can we make a fundamental difference to the rates of late-stage disease where clinical symptoms and societal burden manifest. However, collectively utilizing data, samples, and knowledge amassed by large-scale projects such as the Innovative Medicines Initiative (IMI)-funded European Prevention of Alzheimer's Dementia (EPAD) program will enable the research community to learn, adapt, and implement change. METHOD: In the current article, we define and discuss the substantial assets of the EPAD project for the scientific community, patient population, and industry, describe the EPAD structure with a focus on how the public and private sector interacted and collaborated within the project, reflect how IMI specifically supported the achievements of the above, and conclude with a view for future. RESULTS: The EPAD project was a €64-million investment to facilitate secondary prevention of AD dementia research. The project recruited over 2,000 research participants into the EPAD longitudinal cohort study (LCS) and included over 400 researchers from 39 partners. The EPAD LCS data and biobank are freely available and easily accessible via the Alzheimer's Disease Data Initiative's (ADDI) AD Workbench platform and the University of Edinburgh's Sample Access Committee. The trial delivery network established within the EPAD program is being incorporated into the truly global offering from the Global Alzheimer's Platform (GAP) for trial delivery, and the almost 100 early-career researchers who were part of the EPAD Academy will take forward their experience and learning from EPAD to the next stage of their careers. DISCUSSION: Through GAP, IMI-Neuronet, and follow-on funding from the Alzheimer's Association for the data and sample access systems, the EPAD assets will be maintained and, as and when sponsors seek a new platform trial to be established, the learnings from EPAD will ensure that this can be developed to be even more successful than this first pan-European attempt

Developmentally defined regulation of thyroid hormone metabolism by glucocorticoids in the rat

Glucocorticoids are known regulators of thyroid function in vertebrates. In birds they have clear tissue-specific and age-dependent effects on thyroid hormone metabolism. In mammals, however, few studies exist addressing these aspects using an in vivo model system. We therefore set out to examine the acute effects of a single dose of dexamethasone (DEX) on plasma 3,5,3'-tri-iodothyronine (T(3)) and thyroxine (T(4)) levels, as well as on the activity of the different deiodinases in liver, kidney and brain in the developing rat. In 20-day-old fetuses (E20), glucocorticoids had no effects on circulating thyroid hormone levels despite their clear effects on hepatic and renal deiodinases, thereby indicating that under these conditions circulating thyroid hormone levels are more dependent on thyroidal secretion than on peripheral deiodination. In contrast, in 5-day-old rat pups, DEX did not seem to have any effects on hepatic and renal T(3) production (via the type I deiodinase), whereas type III deiodinase (D3) activity in both these tissues increased significantly. These observations therefore suggested that the DEX-induced increase in circulating T(3) levels is a direct consequence of the increase in plasma T(4) levels. In 12-day-old pups (P12), however, the main effect of glucocorticoids on circulating levels was by increasing inner ring deiodination T(3) through induction of D3 in both liver and kidney. Finally, in the brain, glucocorticoids stimulated thyroid hormone activity only during a short period of time (between E20 and P12) that largely overlaps with the transient window in time during which brain development is thyroid hormone sensitive. This was in contrast to the E20 and P12 brain, where the glucocorticoid-induced changes in type II deiodinase and D3 seemed to favor a status quo in local T(3) availability.status: publishe

Renal and hepatic distribution of type I and type III iodothyronine deiodinase protein in chicken

Iodothyronine deiodinase in vitro activity studies in the chicken showed the presence of type I and type III iodothyronine deiodinase activity in both liver and kidney. Due to the lack of a specific antiserum the cellular localization of the deiodinase proteins could not be revealed until now. In the present study, specific antisera were used to study the renal and hepatic distribution of type I and type III iodothyronine deiodinase protein in the chicken. Immunocytochemical staining of liver tissue led to an immunopositive signal in the hepatocytes in general. Moreover, a zonal distribution could be detected for both enzymes. Maximum protein expression was shown in a thin layer of hepatocytes bordering the blood veins. Although pericentral localization of type I deiodinase protein has been previously reported in the rat, no data were given concerning type III deiodinase protein. In the present study, we report the co-localization of both enzymes in the chicken. Co-expression of the deiodinases was also found in the kidney. Expression of both proteins was associated with the tubular epithelial cells and with the transitional epithelium, and the inner longitudinal and outer circular muscle layers of the ureter. No staining could be detected in the lamina propria or in the fat tissue surrounding the ureter.status: publishe

Thyroid hormone metabolism in poultry

©2000 FAC UNIV SCIENCES AGRONOMIQUES GEMBLOUX. All rights reserved. Thyroid hormone (TH) receptors preferentially bind 3,5,3’-triiodothyronine (T3). Therefore the metabolism of thyroxine (T4) secreted by the thyroid gland in peripheral tissues, resulting in the production and degradation of receptor-active T3, plays a major role in thyroid function. The most important metabolic pathway for THs is deiodination. Another important pathway is sulfation, which is a reversible pathway that has been shown to interact with TH deiodination efficiency. The enzymes catalysing TH deiodination consist of three types. Type I deiodinase (D1) catalyses both outer ring (ORD) and inner ring deiodination (IRD). Type II deiodinase (D2) only catalyses ORD while type III (D3) only catalyses IRD. The three chicken deiodinase cDNAs have been cloned recently. These enzymes all belong to the family of selenoproteins. Ontogenetic studies show that the availability of deiodinases is regulated in a tissue specific and developmental stage dependent way. Characteristic for the chicken is the presence of very high levels of T3inactivating D3 enzyme in the embryonic liver. Hepatic D3 is subject to acute regulation in a number of situations. Both growth hormone and glucocorticoid injection rapidly decrease hepatic D3 levels, hereby increasing plasma T3without affecting hepatic D1 levels. The inhibition of D3 seems to be regulated mainly at the level of D3 gene transcription. The effect of growth hormone on D3 expression persists throughout life, while glucocorticoids start to inhibit hepatic D1 expression in posthatch chickens. Food restriction in growing chickens increases hepatic D3 levels. This contributes to the decrease in plasma T3necessary to reduce energy loss. Refeeding restores hepatic D3 and plasma T3to control levels within a few hours. It can be concluded that the tissue and time dependent regulation of the balance between TH activating and inactivating enzymes plays an essential role in the control of local T3availability and hence in TH activity.status: publishe

The release of growth hormone (GH): relation to the thyrotropic- and corticotropic axis in the chicken

In the chicken and other avian species, the secretion of GH is under a dual stimulatory and inhibitory control of hypothalamic hypophysiotropic factors. Additionally, the thyrotropin-releasing hormone (TRH), contrary to the mammalian situation, is also somatotropic and equally important in releasing GH in chick embryos and juvenile chicks compared to the (mammalian) growth hormone-releasing hormone (GHRH) itself. Consequently, the negative feedback loop for GH release not only involves the insulin-like growth factor IGF-I but also thyroid hormones. In adult chickens, TRH does no longer have a clear thyrotropic activity, whereas its somatotropic activity depends on the feeding status of the animal. In addition, as in mammals, the secretion of GH and glucocorticoids is stimulated by ghrelin, a novel peptide predominantly synthesized in the gastrointestinal tract. Two chicken isoforms of the ghrelin receptor have been identified, both of which are highly expressed in the hypothalamus and pituitary, suggesting that a stimulatory effect may be directed at these levels. GH and glucocorticoids control the peripheral thyroid hormone function by down-regulating the hepatic type III deiodinating enzyme (D3) in embryos (GH and glucocorticoids) and in juvenile and adult chickens (GH). Moreover, glucocorticoids help to regulate T3-homeostasis in the brain during embryogenesis by stimulating the type II deiodinase (D2) expression. This way not only a multifactorial release mechanism exists for GH but also a functional entanglement of activities between the somatotropic-, thyrotropic- and corticotropic axis.status: publishe

The effect of 3,5,3'-triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors

The importance of thyroid hormones (TH) for embryonic development has long been shown in many vertebrates, but is not yet established in pre-hatch teleost models despite the presence of TH, TH receptors and iodothyronine deiodinases. Lack of data about the dynamics of TH metabolism in embryonic stages of fish does not allow to speculate about the involvement and/or role of TH in fish embryonic development. We therefore set up an experiment to examine the effect of 3,5,3'-triiodothyronine (T(3)) on zebrafish (Danio rerio) embryonic development and on the expression of some thyroid hormone-regulated genes as measured by real-time PCR. Maternally derived thyroxine (T(4)) and T(3) were detected throughout embryonic development and total levels remained stable. Thyroid hormone receptor (TR) alpha and beta mRNA were found to be present in early embryos. After an initial fall, TRalpha mRNA levels in the control group increased gradually from 12h post fertilization (HPF) onwards. TRbeta mRNA levels of control embryos were relatively stable during embryonic development, but increased around the hatching period. We also quantified type I (D1) and type II (D2) deiodinase mRNA expression in zebrafish embryos. D1 mRNA levels in the control group gradually increased during development while D2 levels were kept at a low and stable level until hatching. At 75 HPF, a fivefold increase of D2 expression was observed compared to embryonic levels. Exogenous T(3) added to the water (5nM) was taken up by the embryos, causing increased pigmentation and accelerated hatching. T(3) treatment significantly up regulated TRalpha mRNA levels at 48 HPF, while D2 mRNA was significantly down regulated at 75 HPF. Neither TRbeta nor D1 mRNA levels seemed responsive to the treatment. Taken together, these data show that during embryonic development zebrafish already have the necessary regulatory machinery for TH activation and signaling, and that T(3) treatment at that stage indeed influence embryonic development.status: publishe

Regulation of thyroid hormone availability by iodothyronine deiodinases at the blood-brain barrier in birds

It is accepted that type II iodothyronine deiodinase (D2) is predominantly found in brain, where it maintains homeostasis of thyroid hormone (TH) levels. The current study describes the production of a polyclonal D2 antiserum and its use in the comparison of D2 protein distribution with that of type I (D1) and type III (D3) deiodinase protein in the chicken choroid plexus (CP). Immunocytochemistry showed high D2 protein expression in the epithelial cells of the CP, whereas the D1 and D3 proteins were absent. Furthermore, dexamethasone treatment led to an upregulation of the D2 protein in these cells.status: publishe

Control of peripheral thyroid hormone levels by activating and inactivating deiodinases

Book subtitle: FROM MOLECULAR TO INTEGRATIVE BIOLOGYstatus: publishe

The influence of stress on thyroid hormone production and peripheral deiodination in the Nile tilapia (Oreochromis niloticus)

The existence of an interaction between the adrenal/interrenal axis and the thyroidal axis has since long been established in vertebrates, including fish. However, in contrast to mammals, birds and amphibians, no effort was made in fish to expand these studies beyond the level of measuring plasma thyroid hormones. We therefore set out to examine the acute effects of a single dose of dexamethasone (DEX) on plasma thyroxine (T(4)) and 3,5,3'-triiodothyronine (T(3)) levels, as well as on the activity and mRNA expression of the different iodothyronine deiodinases in liver, gills, kidney and brain in Nile tilapia. To take into account the effect of handling stress, this treatment was compared both to a non-treated and to a saline injected group. In general, the observed changes were acute (3 and 6h) while values had returned to control levels by 24h post-injection. Only DEX administration caused an acute drop in circulating T(3) levels compared to non-treated animals, while none of the treatments affected plasma T(4) levels. This indicates that the DEX induced decrease in plasma T(3) levels was not due to a lowered thyroidal hormone production and secretion. DEX injection provoked a decrease in peripheral T(3) production capacity via a decrease in hepatic outer ring deiodination activity (both D1 and D2), whereas T(3) clearance increased by induction of the inner ring deiodinating D3 pathway in liver and in gills. Deiodination activities in kidney and brain were not affected. Effects of saline injection were only observed in liver, where D1 activity decreased and D3 activity increased as in the DEX group, but to a lesser extent. Real-time PCR showed that the changes in hepatic D3 were clearly regulated at the pretranslational level, while this was not confirmed for the other changes. Our results show that both handling stress and DEX injection acutely disturb peripheral deiodination activity in Nile tilapia. However, the effects of the long acting glucocorticoid analogue are more pronounced and result in a decrease in circulating T(3) availability.status: publishe

Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates

The finding that thyrotropin-releasing hormone does not always act as a thyrotropin (TSH)-releasing factor in non-mammalian vertebrates has led researchers to believe that another hypothalamic factor may exhibit this function. In representatives of all non-mammalian vertebrate classes, corticotropin-releasing hormone (CRH) appears to be a potent stimulator of hypophyseal TSH secretion, and might therefore function as a common regulator of both the thyroidal and adrenal/interrenal axes. CRH exerts its dual hypophysiotropic action through two different types of CRH receptors. Thyrotropes express type 2 CRH receptors, while CRH-induced corticotropin (ACTH) secretion is mediated by type I CRH receptors on the corticotropic pituitary cells. The stimulating effect of CRH on both TSH and ACTH release has profound consequences for the peripheral action of both hormonal axes. The simultaneous stimulation of the thyroidal and adrenal/interrenal axes by CRH, possibly fine-tuned by differential regulation of the expression of the different CRH receptor isoforms, provides a potential mechanism for developmental plasticity. (c) 2005 Elsevier Inc. All rights reserved.status: publishe