The effects of thyroid hormones on memory impairment and Alzheimer's disease

Thyroid hormones (THs) have a wide and important range of effects within the central nervous system beginning from fetal life and continuing throughout the adult life. Thyroid disorders are one of the major causes of cognitive impairment including Alzheimer's disease (AD). Several studies in recent years have indicated an association between hypothyroidism or hyperthyroidism and AD. Despite available evidence for this association, it remains unclear whether thyroid dysfunction results from or contributes to the progression of AD. This review discusses the role of THs in learning and memory and summarizes the studies that have linked thyroid function and AD. Eventually, we elaborate how THs may be effective in treating AD by putting forward potential mechanisms.     

Microtubules and brain development: The effects of thyroid hormones

The data accumulated during the past twenty years suggest that thyroid hormones have a direct effect on the differentiation of both the neurons and the glial cell during the critical period of brain development. A fast survey of the available data (which is presented in the introduction of this article) on the mechanism of action of thyroid hormones and on their different effects during brain development suggests that the most dramatic effect of hypothyroidism is a hypoplastic neuropile. Both in vivo, during the critical period of nerve cell differentiation and in vitro, when added to primary cultures of embryonic nerve cells thyroid hormones stimulate neurite outgrowth. Since neurite outgrowth requires massive microtubule assembly the assumption was made that thyroid hormones stimulate nerve cell differentiation by changing the concentration and/or activity of the different proteins (tubulin and “microtubule associated proteins”, MAPs) which co-polymerize to form microtubules.

Preliminary information was obtained by following the kinetics of microtubule assembly in crude brain supernatants. The data showed that: (1) the rate of in vitro microtubule assembly increases with age during brain development; (2) hypothyroidism, when produced in the rat at late pregnancy, slows this evolution; (3) early replacement therapy with thyroid hormones restores normal rates of assembly; (4) the addition of purified MAPs to normal young or 15-day-old hypothyroid brain preparations restores normal rates of polymerization. These and other data suggested that thyroid hormones regulate microtubule assembly by changing the concentration and/or activity of one or more of the MAPs.

Further analysis revealed that striking qualitative changes in MAPs composition occur during brain development. For instance, the TAU fraction, a group of 4–5 proteins with a molecular weight of 60–68 K which is present in adult brain, is absent at early stages of postnatal development: two other entities are present, TAU slow and TAU fast, with different molecular weights, lower activity and different peptide mapping. This latter observation suggests that different TAU genes are expressed during brain development; a conclusion which has been confirmed by cell-free translation of the mRNas coding for these proteins. Analysis of the TAU fraction prepared from hypothyroid rat brains also revealed that a group of TAU proteins. “TAU₃”, is almost missing, whereas thyroid hormone administration markedly increases its concentration. Two-dimensional gel electrophoresis showed that the TAU fraction is composed with more than 15 entities, with at least five of them being under thyroid hormone control.

The precise physiological significance of the heterogeneity of MAPs and of the changes in MAPs composition seen during development and in hypothyroid rat brain remains to be determined. The assumption is made that these changes might be of utmost importance to regulate the number and length of the microtubules, and therefore the number and length of the neurites which are formed during the differentiation process of the different neurons. Thyroid hormones would be in these respects one of the epigenic factors required to synchronize sequentially the expression of the genes coding for these proteins in the different nerve cells.     

Metabolic effects of thyroid hormones at a low temperature in the snake

1. 1.|The metabolic role of the thyroid gland was studied in intact snakes, Naja naja and Ptyas korros treated with tri-iodo-thyronine (T₃) and thyroxine (T₄) and in thyroidectomized (Tx) N. naja kept at 21°C by analyzing tissue composition and glycogen phosphorylase a activity.

2. 2.|Liver weight was unaffected by thyroid hormone injection in both species but decreases in liver glycogen followed T₃ or T₄ injection, and there was an increase in liver glycogen in N. naja. These changes in liver glycogen were accompanied by a decrease in glycogen phosphorylase a activity with T₃ injection. T₃ decreased muscle glycogen in Ptyas and Tx increased it in N. naja.

3. 3.|T₃ increased % liver lipid in Ptyas but not in Naja.

4. 4.|Between species, there were differences in liver weight, blood glucose level, cholesterol level and % muscle lipid.

5. 5.|The results showed that thyroid hormones affected carbohydrate and lipid metabolism at a low temperature of 21°C, although the significance is not known.

The effects of corticosteroid hormones and thyroid hormones on lymphocyte viability and proliferation during development and metamorphosis of Xenopus laevis

Abstract. Metamorphosis in the South African clawed frog, Xenopus laevis , is characterized by a striking loss of lymphocytes in the thymus, liver, and spleen. Changes in the proliferative responses of splenocytes and thymocytes to T cell mitogens and semi-allogeneic cells are also observed at metamorphosis. Because the levels of circulating thyroid hormones (TH) and corticosteroid hormones (CH) increase dramatically during the climax of metamorphosis, we have investigated the possible role of TH and CH as mediators of the changes in lymphocyte numbers or lymphocyte function. Here we report on the in vitro effects of CH and TH on lymphocyte viability and on phytohemagglutinin-P (PHA)-stimulated lymphocyte proliferation at prometamorphosis and climax of metamorphosis. We have observed consistently significant inhibition of proliferation by corticosterone. In contrast, we have observed inconsistent inhibition of proliferation by both thyroxine (T₄) and triiodothyronine (T₃). In short-term studies, the viability of thymocytes and splenocytes was reduced in the presence of CH but not TH.
These observations are consistent with a hypothesis that loss of larval lymphocytes and changes of lymphocyte function at metamorphosis may be due to elevated concentrations of CH rather than TH.
Because CH have been shown to enhance TH-induced effects during metamorphosis, we looked at the combined effects of these agents on PHA-stimulated lymphocyte proliferation. While each agent was inhibitory in several experiments, there was no significantly greater inhibition when splenic lymphocytes were cultured with both.     

Lack of effects of thyroid hormones on human erythrocyte acetylcholine esterase

Effects of thyroid hormones and their metabolites such as L-T1, L-T2, L-T3 and L-T4 on human erythrocyte acetylcholine esterase were studied. The activity of the enzyme of intact erythrocytes was not affected by these hormones, though studied under various conditions. The physiological significance of the binding of these hormones to erythrocyte membranes remains unclear. Our results indicate that the acetylcholine esterase is not a suitable enzyme for cytochemical bioassay for thyroid hormones.     

The effects of selenium depletion and repletion on the metabolism of thyroid hormones in the rat

Rats were fed selenium-deficient (less than 0.005 mg selenium/kg) or selenium-supplemented diets (0.1 mg selenium/kg, as Na2SeO2) for up to five wks from weaning to assess the effects of developing selenium deficiency on the metabolism of thyroid hormones. Within two wks 3:5,3'-triiodothyronine (T3) production from thyroxine (T4) in liver homogenates from selenium-deficient rats was significantly lower compared with the activity in liver homogenates from selenium-supplemented rats. This decreased activity was probably responsible, in part, for the higher T4 and lower T3 concentrations in plasma from the selenium-deficient rats after 3, 4, and 5 weeks of experiment. Repletion of selenium-deficient rats with single intra-peritoneal injections of 200 micrograms selenium/kg body wt. (as Na2SeO3) 5 days before sampling reversed the effects of the deficiency on thyroid hormone metabolism and significantly increased liver and plasma glutathione peroxidase activities. However a dose of 10 micrograms selenium/kg body wt given to rats of similar low selenium status had no effect on thyroid hormone metabolism or glutathione peroxidase activity but did reverse the increase in hepatic glutathione S-transferase activity characteristic of severe selenium deficiency. Imbalances in thyroid hormone metabolism are an early consequence of selenium deficiency and are probably not related to changes in hepatic xenobiotic metabolizing enzymes associated with severe deficiency.     

Effects of magnesium supplementation on blood parameters of athletes at rest and after exercise

The effects of magnesium supplementation on blood parameters were studied during a period of 4 wk in adult tae-kwon-do athletes at rest and exhaustion. Thirty healthy subjects of ages ranging in age from 18 to 22 yr were included in the study. The subjects were separated into three groups, as follows: Group 1 consisted of subjects who did not train receiving 10 mg/kg/d magnesium. Group 2 included subjects equally supplemented with magnesium and exercising 90–120 min/d for 5 d/wk. Group 3 were subject to the same exercise regime but did not receive magnesium supplements. The leukocyte count (WBC) was significantly higher in groups 1 and 2 than in the subjects who did not receive any supplements (p < 0.05). There were no significant differences in the WBC of the two groups under magnesium supplementation. The erythrocyte, hemoglobin, and trombocyte levels were significantly increased in all groups (p < 0.05), but the hematocrit levels did not show any differences between the groups although they were increased after supplementation and exercise. These results suggest that magnesium supplementation positively influences the performance of training athletes by increasing erythrocyte and hemoglobin levels.     

Effect of magnesium supplementation and training on magnesium tissue distribution in rats

The aim of this work is to study the effect of training and Mg supplementation on body pools of Mg and on Mg tissue distribution. Forty male Wistar rats were divided into four groups (n=10): control group (C); trained group (T); Mg-supplemented group (+Mg); and trained and Mg-supplemented group (+MgT). The Mg supplement (100 ppm of Mg) was given in the drinking water for 21 d. The training consisted of swimming during 60% of maximal swimming time obtained in the first session to exhaustion, during 3 wk (5 d a week). The variables measured were: erythrocytes (RBC), hemoglobin (Hb), hematocrit (Hto), total proteins (TP), and Mg in serum, RBC, liver, muscle, bone, and kidney. There was less Mg in liver, muscle, and erythrocyte in trained animals than in control or supplemented animals (T vs C, +MgT vs C and +MgT vs +Mg) (p < 0.01). Trained antimals (T and +MgT) showed higher Mg kidney rates than the untrained ones (p<0.01). There was less bone Mg in control (C) and in supplemented and trained (+MgT) groups than in trained (T) and in supplemented (+Mg) animals (p<0.01). Serum Mg showed a decreasing concentration profile in the following order: +Mg, +MgT, T, C (p<0.01). We conclude that Mg supplementation improves bone and serum Mg levels, but this does not affect Mg status in soft tissues. Maintained exercise leads to a diminution of Mg in the aforementioned soft tissues that is not noticeable in serum, probably provoked by an increase of renal excretion.     

Free and total thyroid hormones in humans at extreme altitude

Alterations in circulatory levels of total T₄ (TT₄), total T₃ (TT₃), free T₄ (FT₄), free T₃ (FT₃), thyrotropin (TSH) and T₃ uptake (T₃U) were studied in male and female sea-level residents (SLR) at sea level, in Armed forces personnel staying at high altitude (3750 m) for prolonged duration (acclimatized lowlanders, ALL) and in high-altitude natives (HAN). Identical studies were also performed on male ALL who trekked to an extreme altitude of 5080 m and stayed at an altitude of more than 6300 m for about 6 months. The total as well as free thyroid hormones were found to be significantly higher in ALL and HAN as compared to SLR values. Both male as well as female HAN had higher levels of thyroid hormones. The rise in hormone levels in different ALL ethnic groups drawn from amongst the southern and northern parts of the country was more or less identical. In both HAN and ALL a decline in FT₃ and FT₄ occurred when these subjects trekked at subzero temperatures to extreme altitude of 5080 m but the levels were found to be higher in ALL who stayed at 6300 m for a prolonged duration. Plasma TSH did not show any appreciable change at lower altitudes but was found to be decreased at extreme altitude. The increase in thyroid hormones at high altitude was not due to an increase in hormone binding proteins, since T₃U was found to be higher at high altitudes. A decline in TSH and hormone binding proteins and an increase in the free moiety of the hormones is indicative of a subtle degree of tissue hyperthyroidism which may be playing an important role in combating the extreme cold and hypoxic environment of high altitudes.     

Short-term effects of thyroid hormones during development: Focus on signal transduction

Extranuclear or nongenomic effects of thyroid hormones are mediated by receptors located at the plasma membrane or inside cells, and are independent of protein synthesis. Recently the αVβ3 integrin was identified as a cell membrane receptor for thyroid hormones, and a wide variety of nongenomic effects have now been shown to be induced through binding of thyroid hormones to this receptor. However, also other thyroid hormone receptors can produce nongenomic effects, including the cytoplasmic TRα and TRβ receptors and probably also a G protein-coupled membrane receptor, and increasing importance is now given to thyroid hormone metabolites like 3,5-diiodothyronine and reverse T₃ that can mimick some nongenomic effects of T₃ and T₄. Signal transduction from the αVβ3 integrin may proceed through at least three independent pathways (protein kinase C, Src or mitogen-activated kinases) but the details are still unknown. Thyroid hormones induce nongenomic effects on at least three important Na⁺-dependent transport systems, the Na⁺/K⁺-ATPase, the Na⁺/H⁺ exchanger, and amino acid transport System A, leading to a mitogenic response in embryo cells; but modulation of the same transport systems may have different roles in other cells and at different developmental stages. It seems that thyroid hormones in many cases can modulate nongenomically the same targets affected by the nuclear receptors through long-term mechanisms. Recent results on nongenomic effects confirm the old theory that the primary role of thyroid hormones is to keep the steady-state level of functioning of the cell, but more and more mechanisms are discovered by which this goal can be achieved.     

Gender-specific effects of thyroid hormones on cardiopulmonary function in SHHF rats.

Spontaneously hypertensive heart failure (SHHF) rats develop hypertension and heart failure. We hypothesized that induction of hyperthyroidism should accelerate development of heart failure in male SHHF rats. Male and female SHHF rats received diets containing desiccated thyroid glands (DTG) or a control diet for 8 wk. Male and female Wistar-Kyoto rats were used as normotensive controls. DTG treatment reduced body weight in male, but not female, SHHF rats but increased body temperature and heart weight-to-body weight ratio in both genders. In DTG-treated male SHHF rats, serum triiodothyronine levels doubled relative to SHHF controls, whereas O2 consumption increased in DTG-treated SHHF rats. Frequency of breathing in air increased in DTG-treated female rats, and ventilation increased in DTG-treated male rats. Ventilatory equivalents exhibited gender differences in SHHF rats, were decreased in both genders by DTG treatment, and reached levels similar to those of Wistar-Kyoto rats. DTG increased heart rate, right ventricular pressure, and contractility in both genders and increased left ventricular pressure in SHHF male rats. These results refute our hypothesis and suggest that cardiopulmonary function of SHHF male rats may be improved by DTG treatment.     

The effect of magnesium supplementation on lactate levels of sportsmen and sedanter

This study was performed to assess how magnesium supplementation affects plasma lactate levels at rest and exhaustion in sportsmen and sedentary. Research was performed on 30 healthy subjects varying between 18-22 years of age for a four-week period. Subjects were separated into 3 groups: Group 1; sedentary taking magnesium supplementation only (10 mg/kg/day) (Mg + S), Group 2; subjects magnesium supplemented + training 90-120 min 5 days a week (Mg + Training), Group 3; training 90-120 min 5 days a week. Lactate levels of the groups were measured 4 times; at rest and exhaustion in the beginning of the research and after the end of the research. At the end of the research, exhaustion measurements both before and after supplement were found significantly higher than rest measurements in terms of lactate levels (p < 0.05). An important decrease was determined in the lactate levels of the 1st and 2nd groups when compared to their first measurements (p < 0.05). The results of this research indicate that lactate increases with exhaustion. However, magnesium supplement may positively affect performance of sportsmen by decreasing their lactate levels.