2008 Tissue Transglutaminase, Protein Cross-linking and Alzheimer's Disease: Review and Views

«Extensive protein cross-linking and aggregation are some of the most common molecular events in the pathogenesis of Alzheimer's disease (AD). Both β-amyloid (Aβ) plaques and neurofibrillary tangles, which are extracellular and intracellular proteinaceous aggregates, respectively, contribute to neuronal death and progressive cognitive decline. Although protein cross-linking has been recognized and extensively studied for many years, the underlying mechanisms are largely unknown. Recent data indicates that tissue transglutaminase (tTG), which catalyzes the cross-linking of a wide spectrum of proteins including Aβ, tau, α-synuclein and neurofilament proteins, may be involved in protein aggregation in AD. Many AD risk factors, such as trauma, inflammation, ischemia and stress, up-regulate tTG protein and activity levels. In this review, we summarize the evidence that tTG plays a role in AD, especially in cross-linking of Aβ, tau, α-synuclein and neurofilament proteins. An experimentally testable hypothesis is that tTG may play a central role in AD pathogenesis and that it provides a conceptual link between sporadic and familial AD through a shared pathogenic pathway.»

2018 Rapid Eye Movement Sleep, Sleep Continuity and Slow Wave Sleep as Predictors of Cognition, Mood, and Subjective Sleep Quality in Healthy Men and Women, Aged 20–84 Years

«Sleep and its sub-states are assumed to be important for brain function across the lifespan but which aspects of sleep associate with various aspects of cognition, mood and self-reported sleep quality has not yet been established in detail. Sleep was quantified by polysomnography, quantitative Electro-Encephalo-Gram (EEG) analysis and self-report in 206 healthy men and women, aged 20-84 years, without sleep complaints. Waking brain function was quantified by five assessments scheduled across the day covering objectively assessed performance across cognitive domains including sustained attention and arousal, decision and response time, motor and sequence control, working memory, and executive function as well as self-reports of alertness, mood and affect. Controlled for age and sex, self-reported sleep quality was negatively associated with number of awakenings and positively associated with the duration of Rapid-Eye-Movement (REM) sleep, but no significant associations with Slow Wave Sleep (SWS) measures were observed. Controlling only for age shows that associations between objective and subjective sleep quality were much stronger in women than in men. Analysis of 51 performance measures demonstrated that after controlling for age and sex, fewer awakenings and more REM sleep were associated significantly with better performance on the Goal Neglect task, which is a test of executive function. Factor analysis of the individual performance measures identified four latent variables labelled Mood/Arousal, Response Time, Accuracy and Visual Perceptual Sensitivity. Whereas Mood/Arousal improved with age, Response Times became slower, while Accuracy and Visual perceptual sensitivity showed little change with age. After controlling for sex and age, nominally significant association between sleep and factor scores were observed such that Response Times were faster with more SWS, and Accuracy was reduced where individuals woke more often or had less REM sleep. These data identify a positive contribution of SWS to processing speed and in particular highlight the importance of sleep continuity and REM sleep for subjective sleep quality and performance accuracy across the adult lifespan. These findings warrant further investigation of the contribution of sleep continuity and REM sleep to brain function.»

«Отметим, что с возрастом выработка грелина снижается. Однако именно грелин способен поддерживать нормальную работу тимуса и продукцию Т-лимфоцитов.То, что грелин замедляет возрастную инволюцию тимуса – это очень важно (Mol Cell Endocrinol. 2011 Jun 20;340(1):44-58..The effects of ghrelin on inflammation and the immune system.)»

2016 Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome

UCB levels had a tendency to decrease with age in the control group (r = −0.274, P = 0.034,

2018 Senolytics Improve Physical Function and Increase Lifespan in Old Age

«To test if senescent cells can directly cause physical dysfunction, we first transplanted senescent (SEN) or control, non-senescent (CON) preadipocytes (also termed adipocyte progenitors or adipose-derived stem cells²³) isolated from luciferase-expressing transgenic (LUC⁺) mice intraperitoneally into syngeneic, young (6-month-old) wild type (WT) animals (Fig. 1a). We induced cellular senescence using 10 Gray (Gy) radiation, which resulted in more than 85% of cells becoming senescent (Supplementary Fig. 1a,b). We transplanted preadipocytes because: 1) the SASP of radiation-induced senescent mouse preadipocytes (Supplementary Fig. 1c,d) resembles that of endogenous senescent cells with aging (Supplementary Fig. 1e)^20,24 and in idiopathic pulmonary fibrosis²⁵; 2) preadipocytes are less immunogenic or subject to rejection than other cell types²⁶; and 3) these cells are arguably the most abundant type of progenitors in humans²⁷ that are subject to cellular senescence. We also used doxorubicin to induce senescence to ascertain if the physiological impact of transplanted senescent cells is limited to the context of radiation-induced senescence: senescent cells induced by doxorubicin developed a SASP similar to that of radiation-induced senescent cells (Supplementary Fig. 1f). Five days after intraperitoneal transplantation of SEN or CON preadipocytes, the cells were mainly located in visceral fat (Fig. 1b,c and Supplementary Fig. 2a,b). Both the SEN and CON transplanted cells remained detectable by in vivo bioluminescence imaging (BLI) for up to 40 days (Supplementary Fig. 2c). Of note, we observed that senescent cells had higher luciferase activity than control non-senescent cells, even though they were from the same LUC transgenic mice (Supplementary Fig.2d).»

2008 A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men.

«Sleep loss is currently proposed to disturb endocrine regulation of energy homeostasis leading to weight gain and obesity. Supporting this view, a reduction of sleep duration to 4 h for two consecutive nights has recently been shown to decrease circulating leptin levels and to increase ghrelin levels, as well as self-reported hunger. We hypothesized that similar endocrine alterations occur even after a single night of sleep restriction. In a balanced order, nine healthy normal-weight men spent three nights in our sleep laboratory separated by at least 2 weeks: one night with a total sleep time of 7 h, one night with a total sleep time of 4.5 h and one night with total sleep deprivation (SD). On a standard symptom-rating scale, subjects rated markedly stronger feelings of hunger after total SD than after 7 h sleep (3.9 +/- 0.7 versus 1.7 +/- 0.3; P = 0.020) or 4.5 h sleep (2.2 +/- 0.5; P = 0.041). Plasma ghrelin levels were 22 +/- 10% higher after total SD than after 7 h sleep (0.85 +/- 0.06 versus 0.72 +/- 0.04 ng mL(-1); P = 0.048) with intermediate levels of the hormone after 4.5 h sleep (0.77 +/- 0.04 ng mL(-1)). Serum leptin levels did not differ between conditions. Feelings of hunger as well as plasma ghrelin levels are already elevated after one night of SD, whereas morning serum leptin concentration remain unaffected. Thus, our results provide further evidence for a disturbing influence of sleep loss on endocrine regulation of energy homeostasis, which on the long run may result in weight gain and obesity.»

2011 The effects of ghrelin on inflammation and the immune system.

«A number of hormone and metabolic mediators signal the brain of changes in the body's energy status and when an imbalance occurs; the brain coordinates the appropriate changes in energy intake and utilization via the control of appetite and food consumption. Under conditions of chronic inflammation and immune activation, there is often a significant loss of body mass and appetite suggesting the presence of shared ligands and signaling pathways mediating "crosstalk" between the immune and neuroendocrine systems. Ghrelin, the endogenous ligand for growth hormone secretagogue receptor (GH-R), is produced primarily by cells in the stomach and serves as a potent circulating orexigenic hormone controlling food intake, energy expenditure, adiposity and GH secretion. The functional roles of ghrelin and other growth hormone secretagogues (GH) within the immune system and under states of inflammatory stress and injury are only now coming to light. A number of reports over the past decade have described ghrelin to be a potent anti-inflammatory mediator both in vitro and in vivo and a promising therapeutic agent in the treatment of inflammatory diseases and injury. Moreover, ghrelin has also been shown to promote lymphocyte development in the primary lymphoid organs (bone marrow and thymus) and to ablate age-associated thymic involution. In the current report, we review the literature supporting a role for ghrelin as an anti-inflammatory agent and immunoregulatory hormone/cytokine and its potential use in the treatment of inflammatory diseases and injury.»

2013 Gilbert's syndrome and the risk of death: a population-based cohort study.

«RESULTS: During the 350 000 PYs of follow up across the Gilbert's and comparison cohorts, there were 1174 deaths. Mortality rates were 24/10 000 PYs in the Gilbert's cohort versus 50/10 000 PYs in the comparison cohort. Mortality rates were around half in patients with Gilbert's syndrome after accounting for sociodemographics and general health indicators (adjusted mortality rate ratio: 0.5 [95% confidence interval; 0.4-0.7; P < 0.001]).

CONCLUSIONS: Mortality rates observed for people with Gilbert's syndrome in the general population are almost half those of people without evidence of Gilbert's syndrome.»

2015 Age and amyloid effects on human central nervous system amyloid-beta kinetics.

Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65.

We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate.

2017 Role of D-galactose-induced brain aging and its potential used for therapeutic interventions.

The effects of D-galactose-induced mitochondrial dysfunction and oxidative stress in the brain. D-galactose oxidized by galactose oxidase to form hydrogen peroxide (H2O2), leading to decrease in superoxide dismutase (SOD) (Hsieh et al., 2009). Increased H2O2 reacts with a reduced form of iron (Fe) to form hydroxide ions (OH-). The H2O2 and OH are both types of reactive oxygen species (ROS) and along with others can cause lipid peroxidation in the cell membranes and impair redox homeostasis, leading to neuronal damage.

In addition, several studies described that D-galactose induced the accumulation of brain mitochondrial DNA mutation (Chen et al., 2011; Du et al., 2012; Du et al., 2015; Zeng et al., 2014) through: 1) decreasing DNA-repairing enzymes (OGG1, pol ᵧ) (Chen et al., 2011), and 2) common deletion of mitochondrial DNA and impairing mitochondrial structures via the NOX-dependent pathway (Du et al., 2015).

Effect of D-galactose-induced apoptosis in the brain. D-galactose
promoted the apoptotic process (Qian et al., 2008). In addition to apoptosis, D-galactose promoted neuro-inflammation and neurodegeneration (Cui et al., 2006). The dosage from which D-galactose started inducing apoptosis was 100 mg- 500 mg/kg/day, duration was from 6 weeks to 9 weeks. (as shown in Table 2)

Effect of D-galactose-induced brain inflammation. D-galactose started inducing inflammation at a dosage of 50mg-180mg/kg/day and duration was from 6 weeks to 60 days.

Therapeutic approaches to brain mitochondrial aging induced by D-galactose:

The first one used R-alpha-lipoic acid which is an antioxidant abundant in yeast, liver, kidney, spinach, broccoli, and potatoes, to treat mitochondrial dysfunction (Long et al., 2007). One of the studies stated that 100 mg/kg/day of R-alpha-lipoic acid is used for prevention but not for intervention, dosage should be increased up to 180mg/kg/day (Inman et al., 2013).

Carvidilol, pioglitazone, curcumin and hesperidin have an antioxidant effect. These drugs have been used as an intervention to reverse D-galactose-induced mitochondrial dysfunction in a dose dependent manner.

The other therapeutic approaches to improve cognition with a dose-independent manner in the D-galactose model were fibroblast growth factor 21 (FGF21), salidroside, and tetrahydropalmatine (Banji et al., 2014; Gao et al., 2015; Kumar et al., 2009; Prakash and Kumar, 2013; Qu et al., 2016; Yang et al., 2016; Yu et al., 2015).

FGF21 acts on its receptors and prevents D-galactose-induced spatial learning and memory impairment by attenuating oxidative stress, inflammatory markers and renovating the activities of antioxidant enzymes and decreasing AGE formation, and TChE activity (Yu et al., 2015).

Many studies have proved that a daily intake of caffeine ameliorated cognitive decline in “non-demented” elderly men and women by the mechanism of reducing synaptic dysfunction, and the reduction in oxidative stress, apoptosis, neuro-inflammation and neurodegeneration (Ritchie et al., 2007; van Gelder et al., 2007).

2018 Diagnostic criteria and contributors to Gilbert's syndrome.

Circulating bilirubin concentration are determined by the rate of heme catabolism, absorption of bilirubin from the gut, hepatic excretion, and trans-epithelial transport from blood to the gut. Therefore, factors affecting these processes can potentially lead to
increased bilirubin concentration - Figure 4. Factors affecting circulating unconjugated bilirubin
concentration.

2018 Rapid Eye Movement Sleep, Sleep Continuity and Slow Wave Sleep as Predictors of Cognition, Mood, and Subjective Sleep Quality in Healthy Men and Wo...

«Sleep and its sub-states are assumed to be important for brain function across the lifespan but which aspects of sleep associate with various aspects of cognition, mood and self-reported sleep quality has not yet been established in detail. Sleep was quantified by polysomnography, quantitative Electroencephalogram (EEG) analysis and self-report in 206 healthy men and women, aged 20-84 years, without sleep complaints. Waking brain function was quantified by five assessments scheduled across the day covering objectively assessed performance across cognitive domains including sustained attention and arousal, decision and response time, motor and sequence control, working memory, and executive function as well as self-reports of alertness, mood and affect. Controlled for age and sex, self-reported sleep quality was negatively associated with number of awakenings and positively associated with the duration of Rapid Eye Movement (REM) sleep, but no significant associations with Slow Wave Sleep (SWS) measures were observed. Controlling only for age showed that associations between objective and subjective sleep quality were much stronger in women than in men. Analysis of 51 performance measures demonstrated that, after controlling for age and sex, fewer awakenings and more REM sleep were associated significantly with better performance on the Goal Neglect task, which is a test of executive function. Factor analysis of the individual performance measures identified four latent variables labeled Mood/Arousal, Response Time, Accuracy, and Visual Perceptual Sensitivity. Whereas Mood/Arousal improved with age, Response Times became slower, while Accuracy and Visual perceptual sensitivity showed little change with age. After controlling for sex and age, nominally significant association between sleep and factor scores were observed such that Response Times were faster with more SWS, and Accuracy was reduced where individuals woke more often or had less REM sleep. These data identify a positive contribution of SWS to processing speed and in particular highlight the importance of sleep continuity and REM sleep for subjective sleep quality and performance accuracy across the adult lifespan. These findings warrant further investigation of the contribution of sleep continuity and REM sleep to brain function.»

2019 Overview of Gilbert's syndrome.

2019 Influence of rapid eye movement sleep on all-cause mortality: a community-based cohort study.

«Over a mean follow-up period of 11.0 ± 3.1 y, 1234 individuals (21.9%) died. In the entire population, reduced REM sleep was significantly associated with increasing all-cause mortality. After adjustment for age, sex, race, body mass index, smoking status, total cholesterol, triglycerides, high-density lipoprotein, history of diabetes and hypertension, and the apnea-hypopnea index, the duration and proportion of REM sleep were found to be significantly associated with all-cause mortality when the lowest and the highest REM quartile groups were compared (hazard ratio, 95% confidence interval: 1.727, 1.434-2.079; 1.545, 1.298-1.839; respectively).»

Inside the Brain: Unraveling the Mystery of Alzheimer&#39;s Disease [HQ] - YouTube

«This 4-minute captioned video shows the intricate mechanisms involved in the progression of Alzheimer's disease in the brain.»

2008 Beta amyloid and Tau proteins (transglutaminase substrates) LECMA - YouTube

WANG«Extensive protein cross-linking and aggregation involving a variety of proteins are commonly occurring molecular processes during the pathogenesis of AD. The initiating factors are likely to be environmental insults (e.g., trauma, inflammation or ischemic damage) that lead to increased tTG activity and increased cross-linking for tau, Aβ and other molecules, which lead to functional impairment, structural lesions characteristic of AD (e.g., plaques and tangles) and eventually neuronal death. If the relationship between increased tTG and deleterious cross-linking of proteins such as α-synuclein, tau and Aβ are critical to AD pathogenesis, therapeutic measures should be developed to manipulate tTG protein and activity levels. » via http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2480529/