Ru-Jing Ren

The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration.

The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer’s disease (AD).

Plasma metabolite profiles of Alzheimer's disease and mild cognitive impairment.

Previous studies have demonstrated altered metabolites in samples of Alzheimers disease (AD) patients. However, the sample size from many of them is relatively small and the metabolites are relatively limited. Here we applied a comprehensive platform using ultraperformance liquid chromatography-time-of-flight mass spectrometry and gas chromatography-time-of-flight mass spectrometry to analyze plasma samples from AD patients, amnestic mild cognitive impairment (aMCI) patients, and normal controls. A biomarker panel consisting of six plasma metabolites (arachidonic acid, N,N-dimethylglycine, thymine, glutamine, glutamic acid, and cytidine) was identified to discriminate AD patients from normal control. Another panel of five plasma metabolites (thymine, arachidonic acid, 2-aminoadipic acid, N,N-dimethylglycine, and 5,8-tetradecadienoic acid) was able to differentiate aMCI patients from control subjects. Both biomarker panels had good agreements with clinical diagnosis. The 2 panels of metabolite markers were all involved in fatty acid metabolism, one-carbon metabolism, amino acid metabolism, and nucleic acid metabolism. Additionally, no altered metabolites were found among the patients at different stages, as well as among those on anticholinesterase medication and those without anticholinesterase medication. These findings provide a comprehensive global plasma metabolite profiling and may contribute to making early diagnosis as well as understanding the pathogenic mechanism of AD and aMCI.

Economic Impact of Dementia in Developing Countries: An Evaluation of Alzheimer-Type Dementia in Shanghai, China

The main objective of this study was to assess the economic cost of Alzheimers disease (AD) in Shanghai, China, as a pilot study for future evaluations. Sixty-seven patients with AD were interviewed, and the information of the AD-related cost and resources used was collected from October 2005 to September 2006. By retrospective analysis, annual costs were calculated and expressed in Chinese renminbi (RMB). Direct cost per patient per year averaged approximately 8,432 RMB (1,058 USD), indirect cost per patient per year was 10,568 RMB (1,326 USD), and annual costs were 19,001 RMB (2,384 USD) per patient per year in this investigation. Total cost was significantly associated with the degree of severity including cognitive function (MMSE) and activity of daily living (ADL). With the increase in the number of persons at risk for developing AD, the economic burden of AD patients in China is significantly heavy.

Neuroprotective effects of PACAP27 in mice model of Parkinson’s disease involved in the modulation of KATP subunits and D2 receptors in the striatum

Pituitary adenylate cyclase activating polypeptide (PACAP) exhibits a protective effect against neural injury in vitro and in vivo. However, it has not been reported whether peripheral intravenous administration of PACAP could confer benefits in animal models of Parkinsons disease (PD). Furthermore, the underlying molecular mechanisms responsible for these effects are poorly understood. In the present experiments, we determined the effects and mechanism of action of intravenously administered PACAP27 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Our results indicate that intravenous injection of PACAP27 offers neuroprotective effects in the MPTP-induced PD mouse model which may not be directly associated with the expression levels of the monoamine transporters. However, this effect may be correlated with its ability to selectively regulate not only K(ATP) subunits, but D2 receptors in the striatum. Our findings suggest that the benefit of PACAP may accompany with changes not only in dopaminergic neurotransmission, but also in cholinergic neurotransmission that are relatively associated with the K(ATP) subunits and D2 receptors in the striatum.

K252a Prevents Nigral Dopaminergic Cell Death Induced by 6-Hydroxydopamine through Inhibition of Both Mixed-Lineage Kinase 3/c-Jun NH2-Terminal Kinase 3 (JNK3) and Apoptosis-Inducing Kinase 1/JNK3 Signaling Pathways

It is well documented that the mitogen-activated protein kinase pathway plays a pivotal role in rats with 6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrostriatal system. Our recent studies have shown that mixed-lineage kinase 3 (MLK3) and apoptosis-inducing kinase 1 (ASK1) are all involved in neuronal cell death induced by ischemia, which is mediated by the MLK3/c-Jun NH2-terminal kinase 3 (JNK3) and ASK1/JNK signaling pathway. To investigate whether these pathways are correlated with 6-OHDA-induced lesion as well, we examined the phosphorylation of MLK3, ASK1, and JNK3 in 6-OHDA rats. The results showed that both MLK3 and ASK1 could activate JNK3 and then subsequently enhance the neuronal death through its downstream pathways (i.e., nuclear and non-nuclear pathway). K252a have wide-range effects including Trk inhibition, MLK3 inhibition, and activation of phosphatidylinositol 3 kinase and mitogen-activated protein kinase kinase signaling pathways through interactions with distinct targets and is a well known neuroprotective compound. We found that K252a could protect dopaminergic neurons against cell program death induced by 6-OHDA lesion, and the phenotypes of 6-OHDA rat model treated with K252a were partial rescued. The inhibition of K252a on the activation of MLK3/JNK3 and ASK1/JNK3 provided a link between 6-OHDA lesion and stress-activated kinases. It suggested that both proapoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play an important role in dopaminergic neuronal death in 6-OHDA insult. Thus, the JNK3 signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of Parkinson disease, and K252a may serve as a potential and important neuroprotectant in therapeutic aspect in Parkinson disease.

The metric properties of Zarit caregiver burden scale: validation study of a Chinese version.

PurposeTo evaluate the Chinese version of the Zarit Burden Interview (ZBI) as an instrument for measuring strain in Chinese caregivers of elderly people with dementia. Design and MethodsThe objective of the present study was to carry out a metric analysis of a Chinese version of ZBI using a cross-sectional study. Patients and their caregivers completed a variety of questionnaires, including the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), the Geriatric Depression Scale (GDS), and the Hamilton Anxiety Scale (HAMA). Cronbach α coefficient was used to assess inter-item consistency, and a split half correlation coefficient was used to determine the internal consistency of the ZBI. Correlations between the ZBI and GDS, and the ZBI and HAMA were assessed for convergent validity. Correlations of the ZBI and MMSE, the ZBI and NPI were also calculated to evaluate the possible correlation of caregiver burden with the severity of cognitive impairment and neuropsychiatric symptoms. ResultsThere were 42 patients with dementia in the study. The intraclass correlation coefficient was 0.89 and the split half correlation coefficient was 0.87. The mean ZBI score was 24.40±14.68. Item-total (corrected) correlation showed significant coefficients (rs>0.33, P<0.05) for most items. There was a significant correlation between the ZBI and GDS (rs=0.57, P<0.001), and between the ZBI and HAMA (rs=0.44, P=0.003). Furthermore, there was a significant positive correlation between the ZBI and NPI, the ZBI and the agitation score, the ZBI and the apathy score, and the ZBI and MMSE. ConclusionsThe Chinese version of ZBI meets some of the basic reliability and validity standards required for health status measures. Further studies could lead to a better understanding of the difficulties experienced by caregivers of patients suffering from dementia in China.

Proteomics of protein post-translational modifications implicated in neurodegeneration.

Mass spectrometry (MS)-based proteomics has developed into a battery of approaches that is exceedingly adept at identifying with high mass accuracy and precision any of the following: oxidative damage to proteins (redox proteomics), phosphorylation (phosphoproteomics), ubiquitination (diglycine remnant proteomics), protein fragmentation (degradomics), and other posttranslational modifications (PTMs). Many studies have linked these PTMs to pathogenic mechanisms of neurodegeneration. To date, identifying PTMs on specific pathology-associated proteins has proven to be a valuable step in the evaluation of functional alteration of proteins and also elucidates biochemical and structural explanations for possible pathophysiological mechanisms of neurodegenerative diseases. This review provides an overview of methods applicable to the identification and quantification of PTMs on proteins and enumerates historic, recent, and potential future research endeavours in the field of proteomics furthering the understanding of PTM roles in the pathogenesis of neurodegeneration.

Validation of the Chinese Version of Addenbrooke's Cognitive Examination-Revised for Screening Mild Alzheimer's Disease and Mild Cognitive Impairment

Background/Aims: As a suitable test to screen for Alzheimers disease (AD) or mild cognitive impairment (MCI), studies to validate the Chinese version of Addenbrookes Cognitive Examination-Revised (ACE-R) are rare. Methods: A total of 151 subjects were recruited and the neuropsychological assessments were employed. One-way analysis of variance and Bonferroni correction were used to compare scores of different psychometric scales. Intraclass correlation coefficient (ICC) and Cronbachs coefficient α were used to evaluate the reliability of psychometric scales. The validity of ACE-R to screen for mild AD and amnestic subtype of MCI (a-MCI) was assessed by receiver operating characteristic (ROC) curves. Results: The Chinese ACE-R had good reliability (inter-rater ICC = 0.994; test-retest ICC = 0.967) as well as reliable internal consistency (Cronbachs coefficient α = 0.859). With its cutoff of 67/68, the sensitivity (0.920) and specificity (0.857) were lower than for the Mini-Mental State Examination (MMSE) cutoff (sensitivity 1.000 and specificity 0.937) to screen for mild AD. However, the sensitivity of ACE-R to screen for a-MCI was superior to the MMSE with a cutoff of 85/86. The specificity of ACE-R was lower than that of the MMSE to screen for a-MCI. The area under the ROC curve of ACE-R was much larger than that of the MMSE (0.836 and 0.751) for detecting a-MCI rather than mild AD. Conclusion: The Chinese ACE-R is a reliable assessment tool for cognitive impairment. It is more sensitive and accurate in screening for a-MCI rather than for AD compared to the MMSE.

The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer's disease.

The growth factor receptor-bound protein 2 (Grb2)-associated binder (Gab) proteins are intracellular scaffolding/docking molecules, and participate in multiple signaling pathways, usually acting as the downstream effector of proteintyrosine kinases (PTKs)-triggered signal transduction pathway. When phosphorylated by PTKs, Gab proteins can recruit several signaling molecules (p85, SHP2, and Crk), and subsequently activate multiple transmitting signals that are critical for cell growth, survival, differentiation and apoptosis. Recently, it has been reported that Gab2 polymorphism is associated with the increase in the risk of Alzheimer’s disease (AD) and is involved in the pathogenesis of AD. This review mainly focuses on the structure and function of Gab2 protein and its role in the pathogenesis of AD. 作为一类骨架/接头蛋白, 生长因子受体结合蛋白2 (Grb2)的相关结合蛋白家族(Grb2-associated binder protein) 参与了细胞内多种信号转导通路, 是酪氨酸激酶(PTKs)激活的下游信号转导通路的关键分子。 Gab2是这个家族的重要成员, 可被PTKs 磷酸化激活, 进而招募多种信号分子(如p85、 SHP2 和Crk), 在细胞增殖、 存活、 分化和凋亡等过程中发挥重要作用。 最近研究表明, Gab2 基因多态性可增加阿尔茨海默病(Alzheimer’s disease, AD)的患病风险, 从而与AD的发病密切相关。 本文拟对Gab2 的结构特点、 相关信号转导通路及其在AD发生过程中可能扮演的角色作一系统综述。The growth factor receptor-bound protein 2 (Grb2)-associated binder (Gab) proteins are intracellular scaffolding/docking molecules, and participate in multiple signaling pathways, usually acting as the downstream effector of proteintyrosine kinases (PTKs)-triggered signal transduction pathway. When phosphorylated by PTKs, Gab proteins can recruit several signaling molecules (p85, SHP2, and Crk), and subsequently activate multiple transmitting signals that are critical for cell growth, survival, differentiation and apoptosis. Recently, it has been reported that Gab2 polymorphism is associated with the increase in the risk of Alzheimer’s disease (AD) and is involved in the pathogenesis of AD. This review mainly focuses on the structure and function of Gab2 protein and its role in the pathogenesis of AD.摘要作为一类骨架/接头蛋白, 生长因子受体结合蛋白2 (Grb2)的相关结合蛋白家族(Grb2-associated binder protein) 参与了细胞内多种信号转导通路, 是酪氨酸激酶(PTKs)激活的下游信号转导通路的关键分子。 Gab2是这个家族的重要成员, 可被PTKs 磷酸化激活, 进而招募多种信号分子(如p85、 SHP2 和Crk), 在细胞增殖、 存活、 分化和凋亡等过程中发挥重要作用。 最近研究表明, Gab2 基因多态性可增加阿尔茨海默病(Alzheimer’s disease, AD)的患病风险, 从而与AD的发病密切相关。 本文拟对Gab2 的结构特点、 相关信号转导通路及其在AD发生过程中可能扮演的角色作一系统综述。

A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population

BACKGROUND LRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimers disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians. METHODS To evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n=361, age>50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD. RESULTS The prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P<0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR=1.378, 95% CI: 1.017-1.867, P=0.039), and the results were not influenced by age, gender, or APOE status (P=0.441, P=0.94, P=0.432, respectively). CONCLUSION Our data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population.