Wen-Yan Kang

PPARγ Agonist Curcumin Reduces the Amyloid-β-Stimulated Inflammatory Responses in Primary Astrocytes

Alzheimers disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes.

DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2–Elk1 pathway in neuroprotection

Loss of function mutations of Park7/DJ‐1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ‐1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ‐1.

Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1.

Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinsons disease (PD) by inducing neurotoxicity. Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remains unclear. This study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also significantly increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). To further investigate the mechanism of SNCAs effect on mitochondrial dynamics, the proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The extracellular signal-regulated kinase (ERK) was confirmed to be involved in the regulation of DLP1 and SNCA-mediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in the future.

P2X7 receptor is critical in α-synuclein–mediated microglial NADPH oxidase activation

Activated microglia are commonly observed in individuals with neurodegenerative disorders, including Parkinsons disease (PD) and are believed to contribute to neuronal death. This process occurs at least due partially to nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation, which leads to the production of superoxide and oxidative stress. α-Synuclein (α-Syn), a key protein implicated in PD pathogenesis, can activate microglia, contributing to death of dopaminergic neurons. Here, microglial cells (BV2) and primary cultured microglia were used to study the role that the purinergic receptor P2X7 plays in recognizing α-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant α-Syn readily activate PHOX, with the A53T form producing more rapid and sustained effects,that is, oxidative stress and cellular injuries. Furthermore, this process involves the activation of phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway. Thus, it is concluded that stimulation of the microglial P2X7 receptor by extracellular α-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD.

Predictive markers for early conversion of iRBD to neurodegenerative synucleinopathy diseases

Objective: To determine the predictive value of clinical assessment and dopamine transporter (DAT) uptake for the early development of neurodegenerative synucleinopathy diseases from idiopathic REM sleep behavior disorder (iRBD) over 5 years in a Chinese population. Methods: Forty-three patients with iRBD were administered clinical assessment tests, and 35 were examined by DAT-SPECT imaging during 2011. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive value of the markers in a follow-up study over 5 years. Results: Eighteen patients (41.9%) developed neurodegenerative synucleinopathy diseases after a median of 4.1 years of prospective follow-up (median interval of 10.5 years from the estimated onset of iRBD symptoms). Patients with higher scores on the Nonmotor Symptom Questionnaire (hazard ratio [HR] 3.11, 95% confidence interval [CI] 1.15–8.40, p = 0.026) and Scale for Outcomes in Parkinson Disease–Autonomic questionnaire (HR 4.46, 95% CI 1.64–12.10, p = 0.003) were more likely to develop neurodegenerative synucleinopathy diseases. Furthermore, the population with decreased 99mTc-TRODAT-1 binding in the left striatum (HR 2.7, 95% CI 1.02–7.14, p = 0.046) and putamen (HR 3.23, 95% CI 1.16–8.33, p = 0.024) had a relatively higher risk of developing neurodegenerative synucleinopathy diseases. Conclusions: Our findings elucidate the predictive value of autonomic dysfunction and DAT uptake in identifying patients with iRBD at a high risk of progressing into neurodegenerative synucleinopathy diseases and could form a basis for future disease-prevention trials.

Salivary DJ-1 could be an indicator of Parkinson's disease progression.

Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinsons disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) (99mTc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of 99mTc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD.

Cognitive impairment and the associated risk factors among the elderly in the Shanghai urban area: a pilot study from China

ObjectivesOur study aimed to investigate the prevalence of cognitive impairment(CI) and the associated risk factors among elderly people in Shanghai urban area, China.MethodsA population-based survey was conducted among people aged 55 years or older in urban areas of Shanghai. Face-to-face interviews were carried out to collect information including demographic characteristics, medical history, and medication use, etc. The validated Chinese version of the Mini-Mental State Examination(MMSE) was used to screen subjects with CI, and the criteria of CI were adjusted for education levels.ResultsA total of 3,176 home-living residents (≥55 years old) were included in the study. Among them, 266 people (102 men and 164 women) were identified as cognition impaired, with a prevalence of 8.38% (266/3,176, 95% CI: (8.26, 8.49)) for both genders, 9.21% (102/1,107,95% CI: (9.18, 9.33)) for men and 7.93% (164/2,069, 95% CI: (7.80, 8.09)) for women, respectively. Furthermore, we found that several significant risk factors, including social factors(education, number of children, marriage status, and family structure), physiological factors (age, blood glucose level, and obesity), factors on living styles(physical exercise, diet & chronic diseases), and genetic factor(ApoE), associated with CI onset.ConclusionsThis study confirms the high prevalence of CI among the elderly population in the Shanghai urban in China, similar to previous epidemiologic studies in Western countries. The putative risk factors associated with CI merit further investigated.

Transcranial sonography of the substantia nigra and its correlation with DAT-SPECT in the diagnosis of Parkinson's disease

INTRODUCTIONS Transcranial sonography (TCS) of the substantia nigra is a new and promising method to diagnose Parkinsons disease (PD) but its effectiveness is controversial. METHODS All 55 PD patients involved in the study underwent single photon emission computed tomography (SPECT) imaging using the labeled dopamine transporter radiotracer (99m)Tc-TRODAT-1 to assess nigrostriatal dopaminergic function. The echogenicity of the substantia nigra was measured by TCS in all patients who received DAT-SPECT scanning. Finally, statistical analysis was carried out to determine the diagnostic accuracy of TCS as well as its correlation with (99m)Tc-TRODAT-1 SPECT, its positive predictive value (PPV), and negative predictive value (NPV). RESULTS Contralateral striatal (99m)Tc-TRODAT-1 uptake was significantly reduced compared to ipsilateral striatal uptake, and had a negative correlation with UPDRS-Ⅲ(r = -0.334, p = 0.013), disease duration (r = -0.393, p = 0.003) and H-Y stage (r = -0.330, p = 0.014). After TCS measurement, the contralateral SN echogenic area was similar to the ipsilateral SN echogenic area (27.77 ± 13.19 vs 25.98 ± 11.94 mm(2), p = 0.402, n = 24). No correlation was identified between TCS and UPDRS-Ⅲ (r = 0.383, p = 0.065), disease duration (r = 0.371, p = 0.075) or H-Y stage (r = 0.259, p = 0.222). The sensitivity and specificity of SN TCS for the diagnosis of PD were calculated as 64.70% and 60% according to DAT-SPECT, respectively, while the positive predictive value and negative predictive value was calculated as 91.67% and 20%, respectively. CONCLUSIONS Compared to DAT-SPECT, TCS is a non-radioactive and convenient procedure to perform. In our investigation, TCS had no correlation with DAT-SPECT. However, the high positive predictive value of TCS highlights its possible utility as a routine diagnostic test.

Association of rapid eye movement sleep behavior disorder with sleep-disordered breathing in Parkinson's disease

OBJECTIVE Rapid eye movement (REM) sleep behavior disorder (RBD) and sleep-disordered breathing (SDB) are two major sleep disturbances observed in patients with Parkinsons disease (PD). However, prior studies exploring the clinical correlations between RBD and SDB in PD have been limited. We aimed to investigate the relationship between RBD and SDB in PD using a case-control study. METHODS A total of 46 PD patients with Hoehn-Yahr stages ranging from 1 to 3 participated in the present study. Participants underwent polysomnography to diagnose the presence of RBD and SDB, and were classified into groups, accordingly. SDB was defined as an apnea-hypopnea index greater than 5. Comparison of clinical and sleep-respiratory parameters was performed among them. RESULTS SDB was more frequent in the RBD group than in the non-RBD group (51.4% vs 9.1%, p = 0.016). PD patients with RBD had significantly reduced mean SaO2 and more severe sleep apnea-related parameters during total sleep and non-REM sleep in comparison with non-RBD PD patients. However, there were no differences on the REM-related apnea/hypopnea variables between participants with and without RBD (p > 0.05). Both the frequency of RBD and RBD screening questionnaire (RBDSQ) scores were higher in the participants with SDB than in the participants without SDB (p <0.05). Furthermore, a significant negative correlation was found between RBDSQ and mean SaO2 in all participants. CONCLUSIONS In PD patients, SDB is more frequent and more severe in patients with RBD than in patients without, and RBD increases the risk of hypoxemia during sleep.

DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy

α-Synuclein misfolding and aggregation play an important role in the pathogenesis of Parkinson’s disease (PD). Loss of function and mutation of the PARK7/DJ-1 gene cause early-onset familial PD. DJ-1 can inhibit α-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type (WT) α-synuclein is mainly degraded by chaperone-mediated autophagy (CMA), and impairment of CMA is closely related to the pathogenesis of PD. Here, we investigated whether DJ-1 could reduce α-synuclein accumulation and aggregation by CMA. DJ-1 knockout mice and DJ-1 siRNA knockdown SH-SY5Y cells were used to investigate the potential mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of α-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased α-synuclein levels. α-Synuclein overexpression activated CMA by elevating the levels of lysosome-associated membrane protein type-2A (LAMP2A), but DJ-1 deficiency suppressed upregulation of LAMP2A. DJ-1 deficiency downregulated the level of lysosomal 70 kDa heat-shock cognate protein (HSC70) but not the levels of that in homogenates. Further studies showed that DJ-1 deficiency accelerated the degradation of LAMP2A in lysosomes, leading to the aggregation of α-synuclein. Our study suggests that DJ-1 deficiency aggravates α-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway.