Specifically, OGT performs an significant role in chromatin remodelling by O-glycosylation (O- GlcNAcylation) of protein targets, including RNA polymerase II, histone deacetylases, and histone 2B. Because O-GlcNAcylation competes with serine/threonine phosphorylation, it perform a vital function in the regulation of enzymatic activity that is strategic for appropriate somatic cell function and embryo viability. Moreover, OGT has been tagged as a cellular nutrient sensor and hence may play an significant role in the protective effects of the placenta on the developing brain from insults such as maternal food deprivation. Furthermore, OGT was identified as an important placental effector of programmatic changes in neurodevelopment, providing a potential mechanism for neurodevelopmental changes resulting from maternal stress in early pregnancy (EPS).The definite scientific fact that brain amyloid is necessary but not adequate for progression of AD insinuates that different disease modifiers are operational. Therefore, although dysfunctional glucose metabolism in the brain is mostly belief to originate from synaptic dysfunction powered by Aβ toxicity, another hypothesis that has come forth is that alterations in metabolism within neurons are rather factors contributing to disease progression. This hypothesis derives support from its well-established correlation with type 2 diabetes mellitus (T2DM), which is well defined as having associated defects in brain glucose metabolism and insulin signalling, being a leading risk factor for the etiology of AD.
Various hypotheses have emphasized that impaired glucose metabolism in the brain may affect the advancement of AD, but an interesting molecular link is a nutrient-sensing pathway that implicates the post-translational modification of nuclear and cytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc). This proposal advocates that impaired glucose metabolism in the brain induced by a toxicity and T2DM leads to decreased brain O-GlcNAc levels. Such a decline in O-GlcNAc levels indicates a breakdown of the protective mechanism of O-GlcNAc in the brain and because of that endues advancement of AD. This hypothesis although still speculative is catchy because O-GlcNAc is entrenched as being a protective stress response and because it is fairly well pitched within the advocated pathological cascade and fits with biochemical alterations within the AD brain. Moreover, the glucose sensitiveness of O-GlcNA coffers an interpretation as to how T2DM can operate at the molecular level as a leading risk factor in AD.
Thyroid hormones (thyroxine [T4], and 3,5,3′ -triiodothyronine [T3]) have major effects on developmental and physiological processes and act on most tissues; the central nervous system been the primary target. During brain maturation, thyroid hormones influence a wide range of developmental processes, such as myelination and neuronal and glial cell differentiation and migration; genes involved in these processes are regulated by thyroid hormones. An altered supply of thyroid hormones in humans can cause irreversible mental retardation and neurological deficits. In adults, thyroid hormones influence mood and behavior, and thyroid diseases can lead to psychiatric manifestations
The significance of thyroid hormones in brain development has been well reported and reviewed for animals. This review leaves no doubt that thyroid hormone deﬁcit or excess during development can have lasting, pervasive, and intense impact on adult neurological function. Some studies also show that comparatively impalpable changes in circulating levels of thyroid hormone in pregnant women can influence the neurological outcome of their children. Therefore, it is vivid that the fetus and neonate are highly sensitive to thyroid hormone.
Empirical scientific prove shows that the fetal rat brain could be a target of thyroid hormones. The newborn rat is developmentally equivalent to the human fetus between the fourth and fifth gestational months, and the newborn human is equivalent to the rat around P10. The thyroid gland develops in the human fetus during the second trimester, whereas in the rat, fetal thyroid function starts on E17.5–18.0. Maternal thyroid is the only source of thyroid hormone prior to the fetal thyroid function. There is a gradual increase in the fetal thyroid hormone with increase in gestational age. In spite of this increase in the fetal thyroid hormone, the maternal contribution persist until birth, with the blood value of T4 standing at 17–18% in the rat, while the value is 30–50% in the human.
Maternal thyroid hormone can be detected in the rat embryo as early as day 3 after uterine implantation, while in human fetus it can be detected in the coelomic fluid. During these early stages, high expression of D3 in the uterine implantation site most likely restricts the level of thyroid hormone that get through to embryonic tissues. Maternal thyroid hormones has been implicated in neuronal migration in the cerebral cortex later in development. Study on P40 of progeny of pregnant rats receiving a low-iodine diet showed alterations of cerebral cortex architecture that could be traced to the time of neuronal migration (normally on E14–E16). Even comparatively moderate decrease of serum T4, evoked by transient administration of a goitrogen (1-methyl-2-mercapto imidazol), during E12–E15 lead to significant alterations of neocortical neuronal migration in the progeny.
It has also been reported that human fetal brain tissues express thyroid hormone receptors (TRs), and receptor occupancy by thyroid hormone is in the range known to produce physiological effects as early as 9 weeks of gestation. The mRNAs encoding the two known TR classes exhibit complex temporal patterns of expression during human gestation, and the mRNAs encoding these TR isoforms are expressed in the human oocyte. This is cogent evidence that active transport of maternal thyroid hormone across the placenta is occurring during this critical period of development and plays up the necessity for maternal thyroid hormones to be at optimal levels at that time. And, therefore, underscore the necessity for maternal T4 levels to be kept within the normal range to guarantee optimal fetal brain development. Because even insignificant reduction in maternal T4 levels in early pregnancy can result in adverse consequences to the offspring.
One of the significant aspect of thyroid hormone action in the brain is the control of the transcriptionally active hormone (T3) concentration. In addition to thyroidal secretion, a large fraction of brain T3 is formed locally from T4 by type 2 deiodinase (D2). This enzyme is expressed in astrocytes and tanycytes. T4 and T3 can be metabolized to reverse T3 and to T2, respectively, by type 3 deiodinase (D3), which is expressed in neurons. Conversion of T4 to T3 in the glial cells might be crucial in the transport of T3 to the cellular targets of action, aiding local control of T3 supply to nearby neurons. In this regard, data have shown that thyroid hormone uptake in the brain is aided by specialised transporters.
Finally, the functional consequences of deﬁcits in thyroid hormone can be highlighted by cretinism, a condition usually associated with severe iodine insufﬁciency in the diet. There are two forms of cretinism based on clinical presentation: neurological cretinism and myxedematous cretinism. Neurological cretinism is characterized by extreme mental retardation, deaf-mutism, impaired voluntary motor activity, and hypertonia. In contrast, myxedematous cretinism is characterized by less severe mental retardation and all the major clinical symptoms of persistent hypothyroidism.
A summary of human fetal and postnatal brain development in relation to thyroid hormones. The approximately equivalent time for birth of the rat is shown as a gray vertical line around midgestation for humans. (A) The ontogeny of the thyroid gland, TSH, thyroid hormone secretion, thyroid nuclear receptor, and D2. D3 is abundant from early stages of embryonic development. Maternal thyroid hormone is available to the fetus during most of gestation, and is presumably the source of T4 as a substrate of D2 in brain, as illustrated by the black arrow. (B) The approximate timing of insults leading to neurological cretinism and myxedematous cretinism, as well as the timing for maternal hypothyroxinemia, prematurity, and congenital hypothyroidism. These features can be correlated with developmental events shown in (A) and (C). (C) The developmental timing of some relevant neurodevelopmental processes shown to be influenced by thyroid hormones in animal models. Part C is based on the article by de Graaf-Peters and Hadders-Algra. 71 Abbreviations: D2, type 2 deiodinase; D3, type 3 deiodinase (Juan, 2007).
The import of thyroid hormone in pre and postnatal brain development has been established as outlined above. However, it is crucial to effectively appraise the mechanisms by which environmental factors can impede with maternal or neonatal thyroid function and thyroid hormone action and as a result affect brain development. On the other hand, although some of the roles of serotonin on neurodevelopment have already been outlined, yet, its impact on placental function at different stages of development is currently under probe.
Furthermore, the fetal brain programming of precise functions is strongly impacted by local glucocorticoid levels dictated by fetal brain 11ß-HSD2, our review illustrated the complex regulation of glucocorticoid action on the multiple targets in the development of the brain, which necessitates further investigations. Concurrently, the combined evidence discussed herein has begun to suggest that recognition of O-linked-N-acetylglucosamine (O-GlcNAc) transferase (OGT) as an significant placental effector of programme alterations in neurodevelopment, offers a possible basic mechanism responsible for neuronal changes due to maternal stress in early pregnancy (EPS).
Based on this review, the placenta is potent micro-environmental player in neurodevelopment as it orchestrates a series of complex maternal–fetal interactions. Maternal insults to this microenvironment will impair these processes and disrupt fetal brain development resulting in the prenatal programming of neurodevelopmental disorders. Based on this review, the placenta is potent micro-environmental player in neurodevelopment as it orchestrates a series of complex maternal–fetal interactions. Maternal insults to this microenvironment will impair these processes and disrupt fetal brain development resulting in the prenatal programming of neurodevelopmental disorders. These findings should inspire advance animal model and human research drive to appraise gene–environment impacts during pregnancy that will target the developmental cause of adult-onset mental disorders.