Alzheimer Disease: Lu Z

Wang B, Jin F, Yang Z, Lu Z, Kan R, Li S, Zheng C, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. · J Mol Neurosci. · Pubmed #17401152 No free full text.

Abstract: Several studies have shown that a common insertion (I)/deletion (D) polymorphism of angiotensin-converting enzyme (ACE) gene may confer an increased risk of late-onset Alzheimer disease (LOAD). However, the result has not been replicated by all studies. In order to clarify the role of the polymorphism for the occurrence of LOAD in Chinese and the possibility of a synergistic effect with the apolipoprotein E allele 4 on the risk of Alzheimer disease, we examined the ACE and APOE genotypes in a Chinese sample consisting of 104 sporadic LOAD patients and 128 healthy controls. An obvious difference of allelic and genotypic distributions of ACE I/D polymorphism between cases and controls was observed (chi2 = 6.61, df = 2, p = 0.037 by genotype; chi2 = 4.67, df = 1, p = 0.031 by allele). And ACE I allele carriers showed an increased risk for LOAD developing (chi2 = 6.59, df = 1, p =0.01, OR = 2.91, 95% CI 1.25-6.77). After stratifying by APOE epsilon 4 status, the increased LOAD risks associated with I allele carriers only in the APOE epsilon 4 noncarriers was seen (chi2 = 4.12, df = 1, p = 0.042). Logistic regression analysis of total subjects demonstrated a more than sevenfold increase in the risk of developing LOAD in subjects carrying both the ACE I allele and the APOE epsilon 4 (OR = 7.39, 95% CI 2.50-21.89, p < 0.001). Our data revealed that ACE I/D polymorphism is considered to be an additional risk factor, which has strong synergistic interaction with APOE epsilon 4 on the risk of LOAD.

Wang B, Jin F, Yang Z, Lu Z, Zheng C, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. · Dement Geriatr Cogn Disord. · Pubmed #17356275 No free full text.

Abstract: Human HSPG2 participates in the formation of amyloid and tau aggregation in Alzheimer's disease (AD). HSPG2 gene is located on a susceptibility region to late-onset AD (LOAD), and considered as a candidate gene for LOAD because of its function and location. We performed an association study between the HSPG2 BamH I polymorphism C/A of intron 6 and LOAD on 104 patients and 127 healthy controls of Chinese origin. The C allele was more prominent in LOAD patients than in controls, though the difference was not statistically significant. Likewise with the stratification of APOE epsilon4 status, no statistical difference was observed between cases and controls. Our findings suggest that this polymorphism may not represent an additional genetic risk factor for LOAD.

Wang B, Jin F, Kan R, Ji S, Zhang C, Lu Z, Zheng C, Yang Z, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. · J Mol Neurosci. · Pubmed #16055944 No free full text.

Abstract: Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer's disease (AD). Because the methylenetetrahydrofolate reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy concentrations, the association between the C677T polymorphism and AD remains inconclusive. To determine whether the MTHFR gene C677T polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we have investigated 104 sporadic LOAD patients and 130 healthy controls. The strong associations of the TT genotype and T-allele with LOAD (p 0.001, OR 5.73 95% CI 1.85-17.72, and p 0.002, OR 1.89 95% CI 1.25-2.86) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the TT genotype only in the APOE epsilon4 noncarriers (chi2=8.92, df=1, p=0.003) and with the T-allele in either group (chi2=5.18, df=1, p=0.023 and chi2=5.53, df=1, p=0.019) were seen. These results suggest that as an APOE epsilon4 allele-dependent risk factor, the MTHFR gene C677T polymorphism is involved in developing LOAD in Chinese.

Zhong Z, Qu Z, Wang N, Wang J, Xie Z, Zhang F, Zhang W, Lu Z. · Guangxi College of TCM, Nanning 530001. · Zhong Yao Cai. · Pubmed #15981887 No free full text.

Abstract: OBJECTIVE: To observe the protective effect of Panax notoginseng saponins (PNS) against pathological lesion of cholinergic neuron in rat model with Alzheimer' s disease (AD). METHODS: The AD rat model was established by intra-peritoneal injection of D-galactose combined with excitatory neurotoxin ibotenic acid (IBA) injection into bilateral nbM. The activity and content of choline acetyltransferase (ChAT), the cell morphology and number of cholinergic neuron in brain were determined by immunohistochemistry analysis. RESULTS: PNS could reduce the pathological lesion of cholinergic neuron, including the level of ChAT and number of cholinergic neuron, as compared with those of model group's rats. CONCLUSION: PNS plays a protective role in pathological lesion of cholinergic neuron in AD rat model.

Kan R, Wang B, Zhang C, Jin F, Yang Z, Ji S, Lu Z, Zheng C, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. · J Mol Neurosci. · Pubmed #15784960 No free full text.

Abstract: Beta-amyloid (Abeta) peptides are derived from the endoproteolytic processing of amyloid precursor protein (APP) and play a key role in the pathogenesis of Alzheimer's disease (AD). Beta-site APP-cleaving enzyme 1 ([BACE1] also known as beta-secretase) is responsible for cleaving APP to generate neurotoxic Abeta peptides in patients with AD. The BACE1 gene is located on chromosome 11q23.3, near the recently identified region with increased lod scores for AD. The biological functional and genetic association studies indicated that the BACE1 gene might be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the BACE1 C786G polymorphism and sporadic LOAD in Chinese, we examined 105 LOAD patients and 130 healthy controls. Our results showed higher frequency of the 786G-allele in LOAD patients (38.6%) than that in controls (28.5%), and a statistical significance was observed for an association of the G-allele with LOAD (odds ratio [OR] = 1.58, 95% confidence interval [CI] 1.07-2.23, p = 0.02). We also found a synergetic interaction between the G-allele and apolipoprotein E allele 4 (APOE e4) status on the risk of LOAD (OR = 1.91, 95% CI 1.23-2.95, p = 0.003). These results suggest that BACE1 gene polymorphism C786G might act as an APOE epsilon4 allele-dependent risk factor for developing LOAD in Chinese.

Kan R, Wang B, Zhang C, Yang Z, Ji S, Lu Z, Zheng C, Jin F, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. · Neurosci Lett. · Pubmed #15531082 No free full text.

Abstract: Serotonergic neurotransmitter system has been implicated in the pathogenesis of Alzheimer's disease (AD). 5-Hydroxytryptamine (5-HT)(6) receptor is mainly expressed in the brain areas involved in cognitive processes. And 5-HT(6) receptor gene (HTR6) variants may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To assess whether HTR6 increases the risk for LOAD, we carried out an association study between the HTR6 polymorphism C267T and sporadic LOAD in Mainland Chinese. An association of C/T genotype with LOAD (OR = 2.10, P = 0.014) was observed. And no statistical difference was found between cases and controls after stratification for APOE epsilon4 status. These data suggest that the HTR6 polymorphism C267T possibly involved in the susceptibility to LOAD as an APOE epsilon4-allele independent risk factor of LOAD.

Wang B, Zhang C, Zheng W, Lu Z, Zheng C, Yang Z, Wang L, Jin F. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. · Neurosci Lett. · Pubmed #15450677 No free full text.

Abstract: A polymorphism (T/C) in intron 2 of the cholesterol 24-hydroxylase (CYP46) gene has recently been reported to be associated with the risk for late-onset Alzheimer's disease (LOAD). To investigate possible involvement of the CYP46 gene and apolipoprotein E (APOE) gene polymorphisms in the manifestation of LOAD, we analyzed 99 sporadic LOAD patients and 113 healthy controls of China. We found an obvious association between CYP46 TT genotype and LOAD (OR = 2.98, 95% CI 1.64-5.44, P < 0.001). A clear increase of the risk to develop LOAD was also observed in subjects carrying both the CYP46 TT genotype and the APOE epsilon4-allele (OR = 12.94, 95% CI 4.26-39.32, P < 0.001). Our data reveal that the polymorphism of CYP46 intron 2 is implicated in the susceptibility to LOAD and a strong synergistic interaction between CYP46 TT homozoygots and APOE epsilon4 carrier status on the risk of LOAD.

Gupta S, Singh R, Datta P, Zhang Z, Orr C, Lu Z, Dubois G, Zervos AS, Meisler MH, Srinivasula SM, Fernandes-Alnemri T, Alnemri ES. · Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. · J Biol Chem. · Pubmed #15294909 links to  free full text

Abstract: Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid beta-precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ domain. We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and beta-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins.

Zhang P, Yang Z, Zhang C, Lu Z, Shi X, Zheng W, Wan C, Zhang D, Zheng C, Li S, Jin F, Wang L. · Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China. · Neurosci Lett. · Pubmed #12951205 No free full text.

Abstract: To investigate the possible involvement of the transferrin (TF) gene polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed the TF and apolipoprotein E (APOE) genotypes of 67 sporadic late-onset AD patients and 131 normal elderly controls in the Chinese population. Our data showed that the TF C1 homozygosity carriers had an increased risk of AD in subjects > or =75 years of age, showing that homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR=3.57, 95% CI, 1.24-10.27, P=0.014). No synergic effects were found between the APOE epsilon 4 allele and TF gene polymorphisms.

Sang H, Lu Z, Li Y, Ru B, Wang W, Chen J. · Department of Cell Biology and Genetics, College of Life Science, Peking University, Beijing 100871, China. · Neurosci Lett. · Pubmed #11602330 No free full text.

Abstract: Tau is a neuronal microtubule-associated protein found predominantly in axons. Hyperphosphorylation of tau reduces the stability of microtubules, which may be a pathogenic mechanism in Alzheimer's disease. To understand the different effects between tau and glycogen synthase kinase 3beta (GSK-3beta) phosphorylated tau on the organization and stability of microtubules, we performed transfection studies on 3T3 cells using EGFP-tau (Enhanced Green Fluorescence Protein-tau) and GSK-3beta to quantify the stability of microtubules. Laser confocal microscope observation revealed that thick and thin microtubule bundles could be induced by tau and GSK-3beta phosphorylated tau. The bundles appeared either to be relatively straight or to form a ring around the circumference of the cell. Both the thick and thin microtubule bundles were resistant to colchicine-induced dissociation, with thick bundles more resistant than thin bundles. The bundles induced by GSK-3beta phosphorylated tau were sensitive to colchicine, and could be reversed by the addition of LiCl, an inhibitor of GSK-3beta.