Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK‐3β) and Alzheimer’s disease risk

Objective – Glycogen synthase kinase‐3β (GSK‐3β) and cyclin‐dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer’s disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK‐3β genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. Methods – In a case–control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3′‐UTR, rs735555) and GSK‐3β (?50, rs334558) polymorphisms on susceptibility to AD. Results – Subjects carrying both the CDK5R1 (3′‐UTR, rs735555) AA genotype and the GSK‐3β (?50, rs334558) CC genotype had a 12.5‐fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01–0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. Conclusion – These data support a role for tau phosphorylation regulating genes in risk for AD.     

SNCA,MAPT, and GSK3B in Parkinson disease: a gene–gene interaction study

Background and purpose: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene–gene interactions between SNCA, MAPT, and GSK3B in association with PD. Methods: Three Caucasian PD patient–control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2‐discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. Results: Our findings indicate that as previously reported, the SNCA rs356219‐G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair‐wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219‐G and MAPT rs1052553‐H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. Conclusions: In the Caucasian patient–control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK‐3β and CREB through PI3‐K/Akt pathways

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK‐3β) and cAMP response element‐binding protein (CREB) through phosphatidylinositol 3‐kinase (PI3‐K)‐dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four‐vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK‐3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3‐K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK‐3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3‐K, compromised the neuroprotective effect of resveratrol and decreased the level of p‐Akt, p‐GSK‐3β and p‐CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro‐survival states of Akt, GSK‐3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3‐K/Akt signaling pathway, subsequently downregulating expression of GSK‐3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.     

δ‐Catenin/NPRAP: A new member of the glycogen synthase kinase‐3β signaling complex that promotes β‐catenin turnover in neurons

Through a multiprotein complex, glycogen synthase kinase‐3β (GSK‐3β) phosphorylates and destabilizes β‐catenin, an important signaling event for neuronal growth and proper synaptic function. δ‐Catenin, or NPRAP (CTNND2), is a neural enriched member of the β‐catenin superfamily and is also known to modulate neurite outgrowth and synaptic activity. In this study, we investigated the possibility that δ‐catenin expression is also affected by GSK‐3β signaling and participates in the molecular complex regulating β‐catenin turnover in neurons. Immunofluorescent light microscopy revealed colocalization of δ‐catenin with members of the molecular destruction complex: GSK‐3β, β‐catenin, and adenomatous polyposis coli proteins in rat primary neurons. GSK‐3β formed a complex with δ‐catenin, and its inhibition resulted in increased δ‐catenin and β‐catenin expression levels. LY294002 and amyloid peptide, known activators of GSK‐3β signaling, reduced δ‐catenin expression levels. Furthermore, δ‐catenin immunoreactivity increased and protein turnover decreased when neurons were treated with proteasome inhibitors, suggesting that the stability of δ‐catenin, like that of β‐catenin, is regulated by proteasome‐mediated degradation. Coimmunoprecipitation experiments showed that δ‐catenin overexpression promoted GSK‐3β and β‐catenin interactions. Primary cortical neurons and PC12 cells expressing δ‐catenin treated with proteasome inhibitors showed increased ubiquitinated β‐catenin forms. Consistent with the hypothesis that δ‐catenin promotes the interaction of the destruction complex molecules, cycloheximide treatment of cells overexpressing δ‐catenin showed enhanced β‐catenin turnover. These studies identify δ‐catenin as a new member of the GSK‐3β signaling pathway and further suggest that δ‐catenin is potentially involved in facilitating the interaction, ubiquitination, and subsequent turnover of β‐catenin in neuronal cells. © 2010 Wiley‐Liss, Inc.     

Synergistic effect of heme oxygenase-1 and tau genetic variants on Alzheimer's disease risk

Oxidative stress plays a role in tau hyperphosphorylation and the development of neurofibrillary tangles (NFT). In Alzheimer's disease (AD) brain, accumulation of hyperphosphorylated tau in NFT is associated with the induction of heme oxygenase-1 (HO-1), a potent antioxidant that downregulates the production of tau. In a case-control study of 300 AD patients and 360 healthy controls, we examined whether the combined gene effects between HO-1 (-413, rs2071746) and tau (5' of exon 1, rs242557) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the HO-1 (-413) TT and the tau (5' of exon 1) AA genotypes had a more than 6.5-time higher risk of developing AD than subjects without these risk genotypes (OR = 6.65, 95% CI 1.12-39.29; p = 0.037). These data support a role for tau-related genes in the risk of AD.     

β‐catenin mediates insulin‐like growth factor‐I actions to promote cyclin D1 mRNA expression,cell proliferation and survival in oligodendroglial cultures

By promoting cell proliferation, survival and maturation insulin‐like growth factor (IGF)‐I is essential to the normal growth and development of the central nervous system. It is clear that IGF‐I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)‐Akt kinases and MAP kinases signal many of IGF‐I‐IGF1R actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether β‐catenin, a molecule that is a downstream target of glycogen synthase kinase‐3β (GSK3β) and plays a key role in the Wnt canonical signaling pathway, mediates IGF‐I actions. We found that IGF‐I increases β‐catenin protein abundance within an hour after IGF‐I‐induced phosphorylation of Akt and GSK3β. Inhibiting the PI3‐Akt pathway suppressed IGF‐I‐induced increases in β‐catenin and cyclin D1 mRNA, while suppression of GSK3β activity simulated IGF‐I actions. Knocking‐down β‐catenin mRNA by RNA interference suppressed IGF‐I‐stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that β‐catenin is an important downstream molecule in the PI3‐Akt‐GSK3β pathway, and as such it mediates IGF‐I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells. © 2010 Wiley‐Liss, Inc.     

GSK3β基因3’-UTR多态性与缺血性脑卒中的关系

目的 探讨糖原合成酶激酶3β(GSK3β)基因3’-UTR多态性与缺血性脑卒中的关系。方法 选择本院2017年3月-2019年3月收治的缺血性脑卒中患者91例作为研究组; 另选择本院2017年3月-2019年3月体检健康者80例作为对照组; 采用PCR法检测GSK3β基因3’-UTR多态性位点rs334558和rs6438552等位基因和基因型频率。结果 研究组ADL评分和认知功能障碍发生率高于对照组(P<0.05); 研究组基因位点rs334558等位基因C分布和基因型频率CC高于对照组(P<0.05); 研究组基因位点rs6438552等位基因C分布和基因型频率CC高于对照组(P<0.05)。结论 GSK3β基因3’-UTR多态性与缺血性卒中存在关系; rs334558和rs6438552位点C等位基因可能为缺血性脑卒中的易感基因     

Attenuation of β‐amyloid‐induced tauopathy via activation of CK2α/SIRT1: Targeting for cilostazol

β‐Amyloid (Aβ) deposits and hyperphosphorylated tau aggregates are the chief hallmarks in the Alzheimer's disease (AD) brains, but the strategies for controlling these pathological events remain elusive. We hypothesized that CK2‐coupled SIRT1 activation stimulated by cilostazol suppresses tau acetylation (Ac‐tau) and tau phosphorylation (P‐tau) by inhibiting activation of P300 and GSK3β. Aβ was endogenously overproduced in N2a cells expressing human APP Swedish mutation (N2aSwe) by exposure to medium containing 1% fetal bovine serum for 24 hr. Increased Aβ accumulation was accompanied by increased Ac‐tau and P‐tau levels. Concomitantly, these cells showed increased P300 and GSK3β P‐Tyr216 expression; their expressions were significantly reduced by treatment with cilostazol (3–30 μM) and resveratrol (20 μM). Moreover, decreased expression of SIRT1 and its activity by Aβ were significantly reversed by cilostazol as by resveratrol. In addition, cilostazol strongly stimulated CK2α phosphorylation and its activity, and then stimulated SIRT1 phosphorylation. These effects were confirmed by using the pharmacological inhibitors KT5720 (1 μM, PKA inhibitor), TBCA (20 μM, inhibitor of CK2), and sirtinol (20 μM, SIRT1 inhibitor) as well as by SIRT1 gene silencing and overexpression techniques. In conclusion, increased cAMP‐dependent protein kinase‐linked CK2/SIRT1 expression by cilostazol can be a therapeutic strategy to suppress the tau‐related neurodegeneration in the AD brain. © 2013 Wiley Periodicals, Inc.     

Interactions between four gene polymorphisms and their association with patients with Parkinson's disease in a Chinese Han population

The four previously reported Parkinson's disease (PD)-related single-nucleotide polymorphisms (SNPs) – rs1775143, rs823114, rs2071746 and rs62063857 – have rarely been studied in Chinese Han populations. To examine the association between these SNPs and PD, we conducted a case-control study of 158 patients with PD and 210 controls. All participants were Chinese Han from Northern China. With covariate adjustment for clinical characteristics, logistic regression analysis revealed no differences in genotype or allele frequencies for the four SNPs. Stratified by age of disease onset, sex, smoking status, duration of disease, baseline UPDRS, Hoehn–Yahr Stage, PD subtypes, scores of Hamilton anxiety scale, Hamilton depression scale and activity of daily living, all of the p values did not remain significant after Bonferroni correction. However, the haplotype rs1775143T-rs823114G-rs2071746T-rs62063857A was associated with increased risk of developing PD (p = 0.003, OR = 456.88, 95% CI: 27.40–7619.75) in our case-control sample set. The haplotype rs1775143T-rs823114G-rs2071746T was also associated with increased risk of developing PD (p = 0.003, OR = 338.43, 95% CI: 20.68–5538.27). Although the haplotype rs1775143T-rs823114G-rs62063857A was associated with increased risk of PD (p = 0.03), the 95% CI was 0.993–22.469. Our data demonstrate that although specific SNPs were not related with PD patients, certain haplotypes were associated with increased risk for PD in the Chinese Han population. These results provide further evidence that the etiology of PD is multifactorial, although the underling mechanism needs further study.     

Immunohistochemical expression of IGF‐I and GSK in the spinal cord of Kii and Guamanian ALS patients

Insulin‐like growth factor‐I (IGF‐I) is a potent survival factor for motor neurons in animals, and glycogen synthase kinase‐3β (GSK‐3β) is suspected to play roles in apoptosis and tau phosphorylation. Here we report the immunological expression of IGF‐I, GSK‐3β, phosphorylated‐GSK‐3α/β (p‐GSK‐3α/β) and phosphorylated‐tau in the spinal cord and hippocampus of Kii and Guam amyotrophic lateral sclerosis (ALS) patients. Sixteen ALS patients (10 Japanese sporadic, 3 Kii and 3 Guam ALS) and 14 neurological controls (10 Japanese and 4 Guamanian) were examined. The immunoreactivity for each antibody was rated by the percentages of positive neurons to total anterior horn neurons in each patient and was analyzed statistically. Many normal‐looking neurons from Japanese sporadic ALS, Kii ALS and Guam ALS patients, as well as from Japanese and Guam controls, were positive for anti‐IGF‐I antibody. A positive correlation between IR scores for anti‐IGF‐I antibody and clinical durations of Japanese sporadic ALS patients was found in this study (P < 0.0001). This suggested that IGF‐I might have a protective effect against ALS degeneration. In Japanese sporadic ALS patients, abnormal as well as normal‐looking neurons showed significant high IR scores for anti‐GSK‐3β antibody than those of controls. Anterior horn neurons from Guam and Kii ALS patients characteristically showed weak staining for anti‐GSK‐3β antibody but were markedly positive for anti‐pGSK‐3α/β antibody compared to those from both Japanese controls and Japanese sporadic ALS patients, and showed the co‐localization of IGF‐I and p‐GSK‐3α/β. This suggested that the IGF‐I signaling pathway in Guam and Kii ALS patients might function to phosphorylate GSK‐3β to protect neurons from ALS degeneration. Neurofibrillary tangles (NFTs) in the hippocampus and spinal cord from Kii and Guam ALS patients showed the co‐localization of PHF‐tau and p‐GSK‐3α/β by a confocal laser scanning technique. The predominant expression of p‐GSK‐3α/β compared to GSK‐3β in spinal motor neurons and the co‐localization of p‐GSK‐3α/β and PHF‐tau in NFT‐laden neurons in the hippocampus and spinal cord were characteristic findings of Kii and Guam ALS patients.     

The peripheral messenger RNA expression of glycogen synthase kinase‐3β genes in Alzheimer's disease patients: a preliminary study

Objective: To explore the peripheral leucocytic messenger RNA (mRNA) expression of glycogen synthase kinase‐3β (GSK‐3β) gene in Alzheimer's disease (AD) patients. Methods: Using TaqMan relative quantitative real‐time polymerase chain reaction, we analyzed leucocytic gene expression of GSK‐3β in 48 AD patients and 49 healthy controls. Clinical data of AD patients were also collected. Results: The mRNA expression level of the GSK‐3β gene was significantly higher in the AD group (3.13 ± 0.62) than in the normal group (2.77 ± 0.77). Correlational analyses showed that the mRNA expression level of GSK‐3β gene in AD patients was associated with the age of onset (P= 0.047), age (P= 0.055), and Behavioral Pathology in Alzheimer's Disease Rating Scale total score (P= 0.062) and subscores: aggressiveness score (P= 0.073) and anxieties and phobias score (P= 0.067). Through multivariate regression model, older age, higher anxieties and phobias score and aggressiveness score were associated with higher mRNA expression level of GSK‐3β gene. Conclusion: In AD patients, the mRNA expression level of the GSK‐3β gene is increased and may be related to age and behavioural pathology in AD.     

GSK3β regulates oligodendrogenesis in the dorsal microdomain of the subventricular zone via Wnt‐β‐catenin signaling

Oligodendrocytes, the myelinating cells of the CNS, are derived postnatally from oligodendrocyte precursors (OPs) of the subventricular zone (SVZ). However, the mechanisms that regulate their generation from SVZ neural stem cells (NSC) are poorly understood. Here, we have examined the role of glycogen synthase kinase 3β (GSK3β), an effector of multiple converging signaling pathways in postnatal mice. The expression of GSK3β by rt‐qPCR was most prominent in the SVZ and in the developing white matter, around the first 1–2 weeks of postnatal life, coinciding with the peak periods of OP differentiation. Intraventricular infusion of the GSK3β inhibitor ARA‐014418 in mice aged postnatal day (P) 8–11 significantly increased generation of OPs in the dorsal microdomain of the SVZ, as shown by expression of cell specific markers using rt‐qPCR and immunolabelling. Analysis of stage specific markers revealed that the augmentation of OPs occurred via increased specification from earlier SVZ cell types. These effects of GSK3β inhibition on the dorsal SVZ were largely attributable to stimulation of the canonical Wnt/β‐catenin signaling pathway over other pathways. The results indicate GSK3β is a key endogenous factor for specifically regulating oligodendrogenesis from the dorsal SVZ microdomain under the control of Wnt‐signaling. GLIA 2014;62:778–789     

FGF20 and Parkinson's disease: No evidence of association or pathogenicity via α‐synuclein expression

Genetic variation in fibroblast growth factor 20 (FGF20) has been associated with risk of Parkinson's disease (PD). Functional evidence suggested the T allele of one SNP, rs12720208 C/T, altered PD risk by increasing FGF20 and α‐synuclein protein levels. Herein we report our association study of FGF20 and PD risk in four patient‐control series (total: 1,262 patients and 1,881 controls), and measurements of FGF20 and α‐synuclein protein levels in brain samples (nine patients). We found no evidence of association between FGF20 variability and PD risk, and no relationship between the rs12720208 genotype, FGF20 and α‐synuclein protein levels. © 2009 Movement Disorder Society     

GSK‐3β inhibitors reverse cocaine‐induced synaptic transmission dysfunction in the nucleus accumbens

Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine‐induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine‐induced hyperlocomotor activity in rats. By employing single‐unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine‐inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N‐methyl‐D‐aspartic acid receptor (NMDAR)‐mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor‐mediate excitatory postsynaptic current (EPSC) were mimicked by the D₁‐like receptor agonist SKF 38393 and blocked by the D₁‐like receptor antagonist SCH 23390, whereas D₂‐like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor‐mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D₁‐like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D₁ receptor–GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine‐induced hyperlocomotion.     

Regulation of GSK‐3β by calpain in the 3‐nitropropionic acid model

Glycogen synthase kinase‐3β (GSK‐3β) is a crucial component in the cascade of events that culminate in a range of neurodegenerative diseases. It is controlled by several pathways, including calpain‐mediated cleavage. Calpain mediates in cell death induced by 3‐nitropropionic acid (3‐NP), but GSK‐3β regulation has not been demonstrated. Here we studied changes in total GSK‐3β protein levels and GSK‐3β phosphorylation at Ser‐9 in this model. The 3‐NP treatment induced GSK‐3β truncation. This regulation was dependent on calpain activation, since addition of calpeptin to the medium prevented this cleavage. While calpain inhibition prevented 3‐NP‐induced neuronal loss, inhibition of GSK‐3β by SB‐415286 did not. Furthermore, inhibition of cdk5, a known target of calpain involved in 3‐NP‐induced cell death, also failed to rescue neurons in our model. Our results point to a new target of calpain and indicate possible cross‐talk between calpain and GSK‐3β in the 3‐NP toxicity pathway. On the basis of our findings, we propose that calpain may modulate 3‐NP‐induced neuronal loss. © 2009 Wiley‐Liss, Inc.     

Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3‐CA1 synapses

Glycogen synthase kinase‐3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long‐term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long‐term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Dietary intake of antioxidant vitamins and risk of Parkinson’s disease: a case–control study in Japan

Background: Antioxidant vitamins are expected to protect cells from oxidative damage by neutralizing the effects of reactive oxygen species. However, epidemiological evidence regarding the associations between antioxidant vitamin intake and Parkinson’s disease (PD) is limited and inconsistent. We investigated the relationship between dietary intake of selected antioxidant vitamins, vegetables and fruit and the risk of PD in Japan using data from a multicenter hospital‐based case–control study. Methods: Included were 249 patients within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self‐administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack‐years of smoking, years of education, body mass index, dietary intake of cholesterol, alcohol, total dairy products, and coffee and the dietary glycemic index. Results: Higher consumption of vitamin E and β‐carotene was significantly associated with a reduced risk of PD after adjustment for confounders under study: the adjusted odds ratio in the highest quartile was 0.45 (95% confidence interval [CI]: 0.25–0.79, P for trend = 0.009) for vitamin E and 0.56 (95% CI: 0.33–0.97, P for trend = 0.03) for β‐carotene. Stratified by sex, such inverse associations were significant only in women. No material relationships were shown between intake of vitamin C, α‐carotene, cryptoxanthin, green and yellow vegetables, other vegetables, or fruit and the risk of PD. Conclusions: Higher intake of vitamin E and β‐carotene may be associated with a decreased risk of PD.     

β‐Amyloid induced effects on cholinergic,serotonergic, and dopaminergic neurons is differentially counteracted by anti‐inflammatory drugs

β‐Amyloid (Aβ) is a small peptide that plays a potent role in synaptic plasticity as well as forms amyloid plaques in Alzheimer's disease (AD). Recent studies suggest that Aβ deposition is deleterious not only in AD, but also in Parkinson's disease (PD) and depression. This Aβ effect is associated with inflammatory processes. However, further evaluation is needed to understand how Aβ and inflammation interact and contribute to the regulation of the cholinergic, serotonergic, and dopaminergic neuronal populations. The aim of the present study was to investigate the effects of Aβ_1–42 on cholinergic neurons of the nucleus basalis of Meynert (which degenerate in AD), on serotonergic neurons of the dorsal raphe nucleus (which play a role in depression), and on dopaminergic neurons of the ventral mesencephalon (which degenerate in PD) in rat organotypic brain slices. Furthermore, we investigated whether anti‐inflammatory drugs (celecoxib, citalopram, cyclooxygenase‐2 inhibitor, ibuprofen, indomethacin, piclamilast) modulate or counteract Aβ‐induced effects. Two‐week‐old organotypic brain slices of the nucleus basalis of Meynert, dorsal raphe nucleus, and ventral mesencephalon were incubated with 50 ng/ml Aβ_1–42 with or without anti‐inflammatory agents for 3 days. Our results reveal that Aβ significantly decreased the number of choline acetyltransferase‐positive cholinergic, tryptophan hydroxylase‐positive serotonergic, and tyrosine hydroxylase‐positive dopaminergic neurons and that anti‐inflammatory drugs partially counteracted the Aβ‐induced neuronal decline. This decline was not due to apoptotic processes (as evaluated by TUNEL, propidium iodide, caspase), oxidative stress (as measured by nitrite, catalase, or superoxide dismutase‐2), or inflammation, but was most likely caused by a downregulation of these key enzymes. © 2012 Wiley Periodicals, Inc.