The Pathological Roles of Ganglioside Metabolism in Alzheimer's Disease: Effects of Gangliosides on Neurogenesis

Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed “GAβ”, has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1–40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1–40 caused a significant reduction of cell number, suggesting that Aβ1–40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder

Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain

The accumulation of Aβ (amyloid β-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Aβ. In the present study, we have examined ganglioside metabolism in the brain of a double-Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Aβ was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1α antigens (cholinergic neuron-specific gangliosides), such as GT1aα and GQ1bα, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Aβ

The dimensionality of fatigue in Parkinson’s disease

Abstract Background Fatigue is a common problem among individuals with Parkinson’s disease (PD). It may occur before the overt symptoms of bradykinesia, rigidity and tremor. Little is understood about how to measure fatigue in PD. Here we determined the dimensionality of the constructs of fatigue. Methods Four recommended scales, the Fatigue Severity Scale, Functional Assessment of Chronic Illness Therapy-Fatigue, Parkinson Fatigue Scale and Visual Analog Fatigue Scale (VAFS) were tested against quality of life measures including cognition, depression, sleep, life orientation, physical activity and PD symptoms in 22 PD subjects and 15 caregivers. Results Fatigue was associated with many quality of life variables, with the PDQ-39 summary index showing the strongest association. PD subjects agreed more strongly than caregivers that they experienced higher levels of fatigue. 27% of PD subjects rated fatigue as one of their top three most bothersome symptoms. The constructs of fatigue was captured within one dimension which explained 67% of the total variance, of which the VAFS showed the highest internal consistency. The highest likelihood ratio gave a cut-off score of < 5.5 on the VAFS. The change in scores required to produce a perceptible difference or is grossly observable ranged between 1.4 and 2.2 points respectively. Conclusion The potential utility of a single measure such as the VAFS in PD that is reliably correlated with quality of life is consistent with the pursuit to develop clinical tests and measurements that are accessible, easy to use and universally interpretable across health science disciplines

Upregulation of GPR109A in Parkinson's disease.

Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD.GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-β, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep.The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted

Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson&rsquo;s Disease: A Single-Center, Randomized, Placebo-Controlled Trial

A six-month double-blind, placebo-controlled randomized study was conducted to ascertain whether low-dose daily niacin supplementation would improve motor symptoms in Parkinson&rsquo;s disease (PD) patients. A total of 47 PD patients were assigned to receive low-dose niacin or a placebo. At the end of the double-blind phase, all participants received open-label niacin for the next six months. All patients were evaluated at baseline, after six months, and after one year of treatment. The primary outcome measure was the Unified Parkinson&rsquo;s Disease Rating Scale III (UPDRS III) scores. Secondary outcome measures were depression, sleep quality, mental flexibility and cognition, and physical fatigue. Niacin treatment was well-tolerated by forty-five subjects. The mean [95% CI] change in UPDRS III scores at six months of placebo was &minus;0.05 [95% CI, &minus;2.4 to 2.32], and niacin was &minus;1.06 [95% CI, &minus;3.68 to 1.57]. From six to twelve months when both groups received open-label niacin supplementation, the average UPDRS III scores significantly decreased for the placebo group by 4.58 [95% CI, &minus;0.85 to 8.30] and the niacin group by 4.63 [95% CI, 1.42 to 7.83] points. Low-dose niacin supplementation is a well-tolerated adjunct therapy and may improve motor function in PD when taken over a longer period

Niacin and Butyrate: Nutraceuticals Targeting Dysbiosis and Intestinal Permeability in Parkinson’s Disease

Dysbiosis is implicated by many studies in the pathogenesis of Parkinson&rsquo;s disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail

Subject characteristics.

<p>Values represent good to excellent coefficient of correlations (<i>p</i><0.05 for all). Empty cells indicate moderate or low correlations (<i>p</i>>0.05).</p><p>Abbreviations are the same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109818#pone-0109818-t001" target="_blank">Table 1</a>.</p><p>*Sleep4 (PD Sleep questionnaire item 4), restlessness of legs or arms at night or in the evening causing disruption of sleep <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109818#pone.0109818-Chaudhuri1" target="_blank">[69]</a>.</p>§<p>PDQ1 (PD Quality of Life questionnaire item 1), difficulty getting around in public.</p>§<p>PDQ3, feeling depressed.</p>§<p>PDQ7, painful muscle cramps or spasms.</p><p>Times woken, number of times woken during EEG night-sleep assessment.</p><p>Actual sleep, sum of EEG light sleep, deep sleep and REM sleep durations.</p><p>Carbidopa, prescribed with dopamine (as Sinemet) to minimize breakdown of levodopa before it crosses the blood brain barrier.</p><p>*High scores indicate less problems.</p>§<p>High scores indicate more problems.</p><p>Subject characteristics.</p

GPR109A expression, NAD/NADH ratio and BHB levels in blood.

<p>(A) Representative GPR109A western blots (B) GPR109A densitometry, (C) NAD/NADH ratio and (D) BHB levels. GPR109A expression and NAD/NADH ratio were tested in the WBCs. The BHB levels were tested in the sera. Young, n = 6; Older, n = 23, PD, n = 22. *<i>p</i> = 0.009 between Age-matched control and PD groups. **<i>p</i> = 0.033 between Age-matched control and PD groups.^§<i>p</i> = 0.071 between Age-matched control and PD groups.</p

Co-localization of GPR109A and microglia in PD and control brain.

<p>Confocal microscopy image of SN of human brain samples showing the glial marker, CD11b (green) co-localized with GPR109A (red). Control sample shows less microglia and GPR109A + cells. Note that all the GPR109+ cells are not co-localized with CD11b maker in control sample. Few neuronal Nuclei (blue) are seen.</p

Sleep in PD.

<p>Sleep Efficiency, ratio of actual sleep divided by total attempted sleep. Actual Sleep, total duration spent sleeping (not including Wake and Time to Z). Total Attempted Sleep, from time to bed to morning rise. Times Woken, number of times subject awaken during night-sleep. Wake Duration, total duration of time spent awake during night-sleep. Light Sleep, light sleep stage. Deep Sleep, deep sleep stage. REM Sleep, rapid eye movement sleep stage. Time to Sleep, the time it takes to fall asleep (a.k.a. sleep latency). *<i>p</i><0.05 between the PD and Older groups. (Young group's data are shown in order to visualize normative values.) Numbers are the effect sizes between the Older and PD groups, based on Cohen's <i>d</i> using averaged standard deviation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109818#pone.0109818-Cohen1" target="_blank">[25]</a>.</p