Melatonin specifically stimulates type-II thyroxine 5'-deiodination in brown adipose tissue of Syrian hamsters

The response of type-II thyroxine 5'-deiodinase (5'-DII) to melatonin treatment was studied in the Syrian hamster. Male hamsters were treated for 15 days with a s.c. pellet containing melatonin, and 5'-DII activity in brown adipose tissue, anterior pituitary gland, Harderian gland and pineal gland was measured using a radioenzymatic technique. Melatonin-treated animals exhibited enhanced 5'-DII activity restricted to brown adipose tissue; the increase was threefold above the values measured in the control group. Serum concentrations of thyroid hormones were unaffected by melatonin treatment. We conclude that the stimulatory effect of melatonin on type-II thyroxine 5'-deiodination is specifically directed to the isoenzyme located in brown adipose tissue and is not accompanied by changes in serum thyroid hormones.     

Central role of brown adipose tissue thyroxine 5'-deiodinase on thyroid hormone-dependent thermogenic response to cold

As judged by the response of uncoupling protein and key enzymes, brown adipose tissue (BAT) is highly dependent upon the local generation of T3 catalyzed by the tissue type II T4 5'-deiodinase (5'-D-II). In hypothyroid rats treated with T3 or T4, the capacity to withstand cold seems better correlated with the normalization of BAT responses than with the liver thyroid status. 5'D-II is activated by cold via sympathetic nervous system (SNS) stimulation, and the activation generates enough T3 to nearly saturate BAT nuclear T3 receptor (NTR) in euthyroid rats. In hypothyroidism, 5'D-II is highly stimulated by the SNS and hypothyroxinemia. In the present studies we have taken advantage of this situation to test 1) the capacity of 5'D-II to maintain nuclear T3 in rats with various degrees of hypothyroxinemia, and 2) the hypothesis that thyroid hormone-dependent BAT-facultative thermogenesis, rather than the effect of thyroid hormone on obligatory thermogenesis (basal metabolic rate), is the basic mechanism by which thyroid hormone confers protection against acute cold exposure. We treated methimazole-blocked rats (undetectable plasma T4 and T3) for a week with either subreplacement doses of T4 (0.5, 1, 2, and 4 micrograms/kg.day) or replacement doses of T4 or T3 (8 or 3 micrograms/kg.day, respectively). Sources and content of BAT nuclear T3 were studied at 25 C and after 48 h at 4 C by labeling the plasmaborne T3 (T3[T3]) with [131I]T3 and the locally generated T3 (T3[T4]) with [125I]T4. Neither the kinetics of nuclear-plasma exchange of T3[T3], the time of appearance of T3[T4] in BAT nuclei, nor NTR maximal binding capacity (0.71 ng T3/mg DNA) was affected by hypothyroidism. Kinetic analyses indicated a maximal BAT NTR occupancy of 40% at euthyroid serum T3 concentrations if T4 is not present. Replacement with T4 normalized both serum T4 and T3, while replacement with T3 normalized serum T3; for all other doses of T4, serum T4 and T3 concentrations were predictably related to the dose. 5'D-II activity decreased with increasing doses of T4, but for each dose of T4, this activity was 2-4 times greater at 4 C than at 25 C. BAT NTR occupancy normalized with 2 micrograms T4/kg in rats maintained at 25 C and with 4 micrograms T4/kg in cold-exposed rats, although in neither condition were serum T4 and T3 normalized nor more than 30% of NTR occupied by plasma T3.(ABSTRACT TRUNCATED AT 400 WORDS)     

The thermogenic role of adipose tissue in the dog

Brown adipose tissue was clearly present in neonatal dogs. In the adult the tissue was superseded by a tissue with the gross characteristics of white adipose. However despite their appearance adult adipose tissue depots may contribute to non-shivering thermogenesis. Regional blood flow measurements using injected radioactive microspheres indicated large increases in blood flow to adipose depots during infusion of noradrenaline. Coupled with blood flow estimations, measurement of arteriovenous differences in dissolved oxygen across the bladder fat depot demonstrated a quantitative increase in oxygen extraction by the depot during noradrenaline infusion. Acute activation of non-shivering thermogenesis in the dog was not associated with increased mitochondrial GDP-binding in adipose tissue. However chronic treatment with a beta-stimulant (LY79730) which increased capacity for non-shivering thermogenesis was associated with increased mitochondrial GDP-binding and cytochrome oxidase activity in peri-renal adipose tissue.     

Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity

A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.     

Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI

The study of brown adipose tissue (BAT) in human weight regulation has been constrained by the lack of a noninvasive tool for measuring this tissue and its function in vivo. Existing imaging modalities are nonspecific and intrinsically insensitive to the less active, lipid-rich BAT of obese subjects, the target population for BAT studies. We demonstrate noninvasive imaging of BAT in mice by hyperpolarized xenon gas MRI. We detect a greater than 15-fold increase in xenon uptake by BAT during stimulation of BAT thermogenesis, which enables us to acquire background-free maps of the tissue in both lean and obese mouse phenotypes. We also demonstrate in vivo MR thermometry of BAT by hyperpolarized xenon gas. Finally, we use the linear temperature dependence of the chemical shift of xenon dissolved in adipose tissue to directly measure BAT temperature and to track thermogenic activity in vivo.Obesity is the result of an imbalance between energy intake and energy expenditure. The latter seems to be modulated, at least in part, by the activity of brown adipose tissue (BAT). BAT is a fatty tissue specialized in cold-induced and diet-induced thermogenesis, a metabolic activity during which this tissue burns fat to produce heat (1). Because of its high “fat-burning” capacity and its ability to regulate glucose homeostasis and insulin sensitivity (2, 3), this tissue is now considered to be the next target for antiobesity drugs (4). However, as interventions that aim to decrease body weight by increasing energy expenditure through BAT volume and/or activity modulations are being investigated (5, 6), the ability to detect this tissue in humans represents an unmet need. Current imaging techniques fail to detect BAT in the target population, obese and overweight subjects, and it is not clear whether this is due to a lack of BAT mass or BAT activity (7). For example, ¹⁸FluoroDeoxyGlucose Positron Emission Tomography (¹⁸FDG-PET), considered to be the gold standard for the detection of BAT activity, can detect BAT activity in morbidly obese and obese subjects only after bariatric surgery or substantial weight loss (8, 9). This is because ¹⁸FDG-PET can only be used to detect active BAT, and in obese subjects, activity is substantially reduced. In addition, the detection of BAT by ¹⁸FDG-PET is performed indirectly, through measurements of BAT uptake of glucose, which is not the primary fuel for BAT thermogenesis. Heat production in BAT is primarily fueled by oxidation of fatty acids released from triglycerides stored in the intracellular fat droplets (10), and, as such, measurements of exogenous glucose or exogenous fatty acid uptake are clearly intrinsically insensitive to BAT thermogenic activity (11, 12).In computed tomography (CT) and ¹H MRI studies, fat fraction measurements are used to differentiate the highly hydrated brown adipose tissue from the less hydrated normal white adipose tissue (WAT) (13–15). Unfortunately, human BAT is a heterogeneous mixture of white and brown adipocytes (16), and partial volume effects that arise from the limited spatial resolution of these imaging modalities make these types of measurements unreliable and nonspecific. Indeed, in one study in which ¹⁸FDG-PET BAT maps and MRI BAT maps were compared, areas that were BAT-positive for ¹⁸FDG-PET had the same fat fraction of nearby areas that were BAT-negative (17). Nonlinear MRI techniques based on intermolecular zero-quantum coherences between water and fat spins can be used to overcome partial volume effects and obtain background-free maps of BAT in lean phenotypes (18). However, in overweight and obese subjects, the strong reduction in tissue hydration and increase in the average distance between water and fat spins would cause a reduction of the already small nonlinear MR signal, making the entire detection unfeasible (18). More importantly, BAT hydration is not a good marker for BAT, as it is highly modulated by tissue thermogenic activity and therefore exhibits very high intersubject and intrasubject variability (19). For example, whereas in lean subjects BAT may have a fat fraction close to 50%, in obese subjects the BAT fat fraction is close to 80%, making it impossible to distinguish this tissue from the normal WAT with conventional fat fraction methods or more sophisticated nonlinear MR techniques.Other less expensive imaging modalities such as infrared thermography and contrast ultrasound have similar problems. BAT thermogenesis is still detected indirectly, either through surface temperature measurements (infrared thermography) that are inherently affected by local changes in tissue blood flow (20) or by measurements of tissue blood flow (ultrasound), which is only partially coupled to BAT thermogenic activity (11) and which exhibits the same insensitivity to the less vascularized lipid-rich BAT of obese phenotypes (21).Our primary goal with this study is to evaluate the possibility to detect BAT tissue and thermogenic activity by using hyperpolarized (HP) xenon gas MRI. In hyperpolarized xenon MRI studies, prior hyperpolarization of the gas through a process called spin-exchange optical pumping (SEOP) is the necessary step to make the gas MR-visible (22). After hyperpolarization, the gas can be inhaled by the subject or by the animal to visualize lung ventilation function (23), xenon gas exchange (23, 24), or other distal organs of interest (25). After inhalation the gas diffuses from the lung airspaces to the lung parenchyma and to the blood. The dissolved gas is then transported to distal organs, where it accumulates proportionally to tissue perfusion rate and to tissue–blood partition coefficient. More interestingly, as xenon diffuses in different tissue compartments, its chemical shift changes, making it possible to differentiate between xenon dissolved in blood and xenon dissolved in tissue or lipids. However, as the amount of xenon that is transferred at any given point in time from the lung airspaces to tissue–blood is relatively small, and as the T1 relaxation time of xenon in blood is relatively short, imaging of distal organs by hyperpolarized xenon gas remains a major challenge.Here we capitalize on the lipophilic nature of xenon and on the strong increase in blood flow to brown fat that occurs during stimulation of thermogenic activity to detect the highly vascularized BAT (26). In addition, we measure and use the chemical shift temperature coefficient of xenon dissolved in adipose tissue to directly detect its thermogenic activity in vivo.     

Thyroxine 5'-deiodinase type II activity in chick pineal and Harderian gland: Nyctohemeral rhythmicity and its regulation by noradrenergic input

Abstract: Circadian rhythmicity of type II thyroxine 5′-deiodinase (5′-D) activity was studied in the pineal gland and Harderian glands of chicks. Only Harderian 5′-D activity showed a nyctohemeral rhythmicity with a maximal peak during the day time (1300), while no rhythm of enzyme activity was found in the pineal gland. Besides type II 5′-D activity, we found high basal levels of the type I isoenzyme in both glands; this activity was specifically suppressed by the addition of 6-n-propyl-thiouracil (PTU). However, day-night differences in Harderian 5′-D activity were maintained even after the addition of PTU. This activity was not affected for either continuous light exposure or darkness during the day. 5′-D activity seems to be regulated by the noradrenergic input, since the enzymatic activity was stimulated by a β-adrenergic agonist, isoproterenol, and by the α-adrenergic agonist, phenylephrine, in both pineal and Harderian glands. Both drugs affected 5′-D activity in the Harderian gland by stimulating the enzyme activity over basal levels.     

The role of brown adipose tissue in human obesity

It is widely accepted that newborn humans are provided with brown adipose tissue (BAT) and that adult humans lack, or have only a small amount, of it. Therefore the physiological role of BAT in humans is debated. It is quite clear that BAT in rodents has an important role in the prevention and therapy of obesity and diabetes and specific drugs can induce BAT development in adult animals. New concepts regarding the biology of adipose tissues in mammals have been developed during the last years leading to the hope for the development of BAT in human adults as a new challenge for the treatment of obesity and related diseases. These new concepts are basic to understanding the above-proposed therapeutic strategy and are the concept of the adipose organ and the concept of transdifferentiation. In this paper these new concepts will be explained together with a review of available scientific data on human BAT.     

Inhibition of 5'-deiodination of thyroxine suppresses the cold-induced increase in brown adipose tissue messenger ribonucleic acid for mitochondrial uncoupling protein without influencing lipoprotein lipase activity

Young adult male and female Djungarian hamsters were exposed to ambient temperatures of 23 or 0 C for 12 h; half of the animals in each group were treated with iopanoic acid to suppress the peripheral conversion of T4 to the thermotropically active thyroid hormone T3 by the enzyme 5'-deiodinase (5'D). Brown adipose tissue (BAT) mRNA for uncoupling protein (UCP), BAT lipoprotein lipase (LPL) activity, and 5'D activity were measured at the conclusion of the study. A temperature of 0 C produced large rises in 5'D and LPL activities and a similar large increase in UCP mRNA within the 12-h exposure period. When 5'D activity was inhibited with iopanoic acid, mRNA for UCP was reduced, while LPL activity was unaffected. The results show that the optimal production of mRNA for BAT UCP depends on the availability of T3; however, T3 is not required for the cold-induced activation of LPL activity in BAT.     

Comparison of kidney and brown adipose tissue iodothyronine 5'-deiodinases

We have examined the influence of assay conditions on the 6-n-propyl-2-thiouracil (PTU) sensitivity of the iodothyronine 5'-deiodinase in brown adipose tissue (BAT) from hypothyroid rats. These results were compared with similar studies of 5'-deiodinase activity in kidney microsomes from euthyroid animals. Even though BAT microsomes contain largely type II (PTU-insensitive) deiodinase activity, the 5'-deiodination of T4 can be inhibited by PTU if the dithiothreitol (DTT) concentration in the assay is reduced to 5 mM or less. The apparent Ki for PTU of BAT microsomes was 4.3 mM at 5.0 mM DTT and 0.41 mM at 0.5 mM DTT. The kinetics of inhibition were noncompetitive. With kidney microsomes, PTU inhibition of rT3 5'-deiodination was both time and enzyme/substrate ratio dependent. For example, using 1 microgram microsomal protein, 2 nM rT3, and 5 mM DTT, the inhibitory effect of PTU was not maximal until 12 min after PTU addition. At stable reaction velocities PTU inhibition was uncompetitive, and the Ki was about 1 microM. Deiodination by kidney microsomes was completely inhibited by 50 microM PTU. Even though it is possible to inhibit the type II 5'-deiodinase activity with high concentrations of PTU (in the presence of low DTT concentrations), the deiodinase in kidney is about 1000-fold more sensitive to PTU. By these criteria the kidney microsome 5'-deiodinase is type I.     

Iodothyronine 5'-deiodinase in brown adipose tissue: thiol activation and propylthiouracil inhibition

Brown adipose tissue (BAT) of hypothyroid rats contains a low Km (type II) iodothyronine 5'-deiodinase (I-5'D) that has been characterized as being insensitive to inhibition by propylthiouracil (PTU), based mainly on observations with homogenates prepared in a medium containing 10 mM dithiothreitol (DTT) and enzymatic assays in the presence of 20 mM DTT in vitro. In the studies reported herein, BAT homogenates from hypothyroid rats prepared in a DTT-free medium were found to contain I-5'D activity at 20 mM DTT, comparable to that in homogenates prepared in a DTT-containing medium, and were activated by submillimolar concentrations of DTT with an EC50 of approximately 0.5 mM. Almost all of the homogenate activities could be accounted for in microsomal preparations. The activity was substantially inhibited by 1 mM PTU. The PTU inhibition was progressively alleviated with increasing concentrations of added DTT and was not seen at DTT concentrations higher than 10 mM. At 250 microM DTT, the Km and maximum velocity values for rT3 and T4 were 2.9 and 1 nM and 70 and 200 fmol/mg protein X h, respectively, with a Ki for PTU of approximately 200 microM. On administration of PTU in vivo (2 mg/100 g BW; 1 h before killing) and subsequent assay at 250 microM DTT, the I-5'D in the homogenates was about 50% inhibited, and the microsomes showed a state of persistent inhibition, with activity levels about 70% of the control value. The data show that BAT type II I-5'D can be substantially activated at submillimolar concentrations of DTT, and this activation is sensitive to inhibition by PTU administered both in vitro and in vivo.     

Changes in body composition, brown adipose tissue activity and thermogenic capacity in BN/BiRij rats undergoing senescence

Metabolic rate, thermogenesis, brown adipose tissue (BAT) activity, and body composition were followed in ageing rats (female BN/BiRij) at 3 to 35.5 months of age. Colonic temperatures were similar in rats at 3 to 23 months of age (37.1–37.6°C), but significantly reduced (36.3°C) in those aged 36 months. Resting oxygen consumption (VO₂), corrected for body size, was comparable in all groups, but the thermogenic response to noradrenaline was significantly reduced with age. BAT mass was unaffected by age, but brown fat protein content, specific mitochondrial cytochrome oxidase activity and thermogenic activity (assessed from mitochondrial purine nucleotide binding) all declined markedly with age.

Carcass analysis revealed a fall in body protein in very old (35.5 month) rats, but body fat content increased up to 23 months of age and thereafter declined.     

Ovine pineal alpha 1-adrenoceptors: characterization and evidence for a functional role in the regulation of serum melatonin

Plasma melatonin in sheep increases to nocturnal levels rapidly (10-20 min) after dark onset. This increase is blocked by iv prazosin (1 mg), but not propranolol (6 mg). Prazosin also blocks the elevation in pineal melatonin content after dark onset, but does not significantly alter the rise in N-acetyltransferase activity or the elevation in pineal N-acetylserotonin content. Since the nocturnal elevation in N-acetyltransferase, a neurally regulated event, was unaltered, this suggests that prazosin does not significantly impair the transmission of neural signals from the eye to the gland, but does act on pineal alpha 1-adrenoceptors to block melatonin production. This is supported by binding studies in ovine pineal membranes using [125I] iodo-2-[beta-(4-hydroxyphenyl)ethylaminomethyl]tetralone, which revealed that binding is rapid, reversible, saturable, and stereo-specific. Saturation studies indicated the presence of a single class of binding sites, with an equilibrium binding constant (Kd) of 32 +/- 6 pM and a maximum binding of 139 +/- 19 fmol/mg protein. The relative potencies of several adrenergic agonists and antagonists in competition studies indicated that the receptor belongs to the alpha 1-subclass of adrenoceptors. Together, these data suggest that melatonin synthesis in the sheep pineal gland is controlled in part by an alpha 1-adrenoceptor mechanism at a step beyond N-acetylation.     

Effects of cycloheximide and aminophylline on 5-methoxytryptophol and melatonin contents in the chick pineal gland

The chick pineal gland rhythmically synthesizes two 5-methoxyindoles, melatonin and 5-methoxytryptophol. These rhythms are circadian in nature and have opposite phases. The aim of this study was to determine the effects of cycloheximide, a protein synthesis inhibitor, and aminophylline, an inhibitor of phosphodiesterase, on 5-methoxytryptophol content in the chick pineal gland and to compare this with the drugs' action on pineal melatonin production. Inhibition of melatonin biosynthesis by cycloheximide (1 mg/kg, i.p. ), revealed by a marked reduction in the nighttime activity of serotonin N-acetyltransferase (AA-NAT; a key regulatory enzyme in melatonin synthesis) and melatonin concentrations, was accompanied by a significant increase in 5-methoxytryptophol content. In contrast, administration of aminophylline (100 mg/kg, i.p.) to light-exposed chicks significantly increased pineal AA-NAT activity and melatonin levels and decreased 5-methoxytryptophol concentrations. It is concluded that in the chick the production of pineal 5-methoxytryptophol and melatonin is inversely correlated.     

Thyroxine and tri-iodothyronine differently affect uncoupling protein-1 content and antioxidant enzyme activities in rat interscapular brown adipose tissue

The activity of the antioxidant enzymes copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and catalase (CAT), as well as mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) activity, uncoupling protein-1 (UCP1) content, catecholamine degrading enzyme monoamine oxidase (MAO) activity and malonyl dialdehyde (MDA) concentration were studied in rat interscapular brown adipose tIssue (IBAT). Rats were treated with either thyroxine (T4) or tri-iodothyronine (T3) for five days and then exposed to cold (4 degrees C, 24 h) or housed at room temperature (22 degrees C). Under basal conditions, T3 treatment significantly increased UCP1 content and MnSOD activity whereas CuZnSOD, CAT and MAO activities were significantly decreased. Thyroxine treatment significantly decreased IBAT CAT activity while MDA levels markedly increased. Cold exposure induced a significant augmentation of UCP1 content and MnSOD and mGPDH activities only in animals that were rendered hyperthyroid by T4 treatment. In T3-treated animals acutely exposed to cold stress, MDA concentration, an indicator of lipid peroxidation, was significantly higher compared with that of T3-treated animals housed at room temperature. However, in T4-treated animals, MDA concentrations were markedly lower. These results show that T4 and T3 differently affect IBAT parameters studied not only under basal but also under cold-stimulated conditions.     

Role of extracellular calcium on the regulation of melatonin synthesis in the Syrian hamster pineal gland

The role of extracellular calcium on the induction of cyclic AMP production, N-acetyltransferase (NAT) activity and melatonin synthesis, induced by forskolin, was investigated in Syrian hamster pineal glands. Pineals were removed from hamsters killed either in the first half of the normal dark period or late in the dark period. Forskolin immediately increased NAT activity and melatonin levels only when the glands were collected late in the dark period, while in the first half of the dark phase, hamster pineals responded to forskolin with an increase of NAT activity and melatonin production only after 6 hr of incubation. The absence of calcium prevented the induction of melatonin synthesis by forskolin only when glands were collected early in the dark phase and incubated for 6 hr. In the second half of the normal dark period removal of calcium markedly decreased NAT activity and melatonin levels in glands incubated with forskolin for either 4 or 6 hr. However, the absence of extracellular calcium had no significant effect on the induction of cyclic AMP production by forskolin in pineals collected either early in the dark period or late in the dark phase. These data indicate that at least part of the action of extracellular calcium is indirect and that it affects steps in the induction of melatonin synthesis beyond the accumulation of cAMP.     

Daily variation in the concentration of 5-methoxytryptophol and melatonin in the duck pineal gland and plasma

The duck pineal gland rhythmically produces two 5-methoxyindole compounds, i.e. 5-methoxytryptophol and melatonin. 5-Methoxytryptophol levels are low at night and high during the day, while melatonin concentrations are high at night and low during the day. The melatonin rhythm reflects oscillations in the activity of serotonin N-acetyltransferase (AA-NAT; a penultimate and key regulatory enzyme in the melatonin biosynthetic pathway). The activity of hydroxyindole-O-methyltransferase (HIOMT; an enzyme involved in the synthesis of both 5-methoxytryptophol and melatonin) does not exhibit any significant rhythmic changes throughout the 24-hr period. Plasma levels of melatonin exhibited daily changes that were parallel to fluctuations in pineal melatonin content. Although plasma concentrations of 5-methoxytryptophol were low in ducks, they showed daily variations. The mean 5-methoxytryptophol concentration between zeitgeber time 9 (ZT9) and ZT15 was 2.4-times higher than the mean value for samples collected between ZT18 and ZT3. These findings indicate that in the duck the pineal production of 5-methoxytryptophol and melatonin may be inversely correlated.     

The human pineal gland and melatonin in aging and Alzheimer's disease

The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.