Zhong-Chen Wu

Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population

Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimers disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1). These studies have been conducted almost exclusively in white populations and it is unclear whether these observations generalize to populations with different ethnicities.

Implication of CLU gene polymorphisms in Chinese patients with Alzheimer's disease.

BACKGROUND Clusterin (also called apolipoprotein J) has a potential central role in the pathogenesis of Alzheimers disease (AD). Recently, two genome-wide association studies have identified three variants in CLU gene encoding clusterin associated with AD risk in Caucasians, while there are no studies on the association of CLU with AD risk in Asians. METHODS The study investigated 324 sporadic late-onset AD (LOAD) and 388 healthy controls matched for sex and age in a Han Chinese population. Three common genetic variants (rs2279590, rs11136000 and rs9331888) in CLU gene were genotyped using MALDI-TOF mass spectrometry. RESULTS The minor allele (G) of the rs9331888 polymorphism within CLU was significantly associated with an increased risk of LOAD (OR=1.39, 95% CI=1.13-1.72, P=0.002). Logistic regression analysis revealed that the rs9331888 polymorphism presented strong associations with LOAD in the dominant, recessive and additive models. No significant differences in genotype and allele frequencies of the rs2279590 and rs11136000 polymorphisms were found between LOAD patients and controls. Haplotype analysis identified a risk haplotype (CCG) (OR=1.66) and a protective haplotype (CCC)(OR=0.70). CONCLUSIONS Our findings implicate CLU as a susceptibility gene for LOAD in Han Chinese.

Targeting the mTOR Signaling Network for Alzheimer's Disease Therapy

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that can sense environmental stimuli such as growth factors, energy state, and nutrients. It is essential for cell growth, proliferation, and metabolism, but dysregulation of mTOR signaling pathway is also associated with a number of human diseases. Encouraging data from experiments have provided sufficient evidence for the relationship between the mTOR signaling pathway and Alzheimer’s disease (AD). Upregulation of mTOR signaling pathway is thought to play an important role in major pathological processes of AD. The mTOR inhibitors such as rapamycin have been proven to ameliorate the AD-like pathology and cognitive deficits effectively in a broad range of animal models. Application of mTOR inhibitors indicates the potential value of reducing mTOR activity as an innovative therapeutic strategy for AD. In this review, we will focus on the recent process in understanding mTOR signaling pathway and the vital involvement of this signaling pathway in the pathology of AD, and discuss the application of mTOR inhibitors as potential therapeutic agents for the treatment of AD.

Clusterin in Alzheimer's disease.

Clusterin, also known as apolipoprotein J, is a ubiquitous multifunctional glycoprotein. Following its identification in 1983, clusterin was found to be clearly increased in Alzheimers disease (AD). Later research demonstrated that clusterin could bind amyloid-beta (Abeta) peptides and prevent fibril formation, a hallmark of AD pathology. In addition to preventing excessive inflammation, intracellular clusterin was found to reduce apoptosis and oxidative stress. Although early studies were inconclusive, two recent large-scale genome-wide association studies (GWAS) independently identified variants within the clusterin gene as risk factors for developing AD. This review focuses on the characteristics of clusterin and possible mechanisms of its relationship to AD.

Complement receptor 1 polymorphisms and risk of late-onset Alzheimer's disease

The amyloid beta-protein (Abeta)-induced complement system activation plays an important role in Alzheimers disease (AD). Complement receptor 1 (CR1) is thought to contribute to Abeta clearance. A recent large genome-wide association study (GWAS) has identified significant association of two single nucleotide polymorphisms (SNPs) (rs6656401 and rs3818361) in the CR1 gene with AD in Caucasians. Here, we performed a case-control study to clarify whether the risk for sporadic late-onset AD (LOAD) might be influenced by these polymorphisms in a large Chinese cohort consisting of 254 patients and 357 healthy controls. The results revealed that there were significant differences in genotype (P=0.02) and allele (P=0.007) frequencies of the SNP rs6656401 but no in rs3818361 between AD patients and controls. The A allele of rs6656401 was associated with an increased risk of LOAD (P=0.007, odds ratios/OR =1.652). In the subgroup of APOE epsilon4 non-carriers, both the A of rs6656401 and T allele of rs3818361 were observed to be significantly higher in case than in controls (P=0.002 and P=0.035, respectively). For rs6656401, the logistic regression analysis revealed that the (AA +AG) genotypes has a 2.4-fold increased risk compared with the GG genotype (P=0.049). Haplotype analysis identified the AT haplotype to increase the risk of LOAD (P=0.03, OR=2.44). This study provides the evidence that variations in the CR1 gene play an important role in the pathogenesis of sporadic LOAD in the Han Chinese population.

Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease

Interleukin-33 (IL-33), a newly described member of the IL-1 family, is located on chromosome 9p24, a chromosomal region of interest in Alzheimers disease (AD) defined by many genome-wide studies. Three intronic rs1157505, rs11792633, and rs7044343 single nucleotide polymorphisms (SNPs) within IL-33 have recently been reported to be associated with risk of AD in Caucasian populations. In order to assess the involvement of the IL-33 polymorphisms in the risk of developing late onset AD (LOAD), we analyzed the genotype and allele distributions of these 3 polymorphisms in 704 Han Chinese subjects. The minor alleles of the rs11792633 polymorphism within IL-33 was significantly associated with a reduced risk of LOAD (odds ratio [OR] = 0.73, p = 0.005). Furthermore, rs11792633 polymorphism was still strongly associated with LOAD (dominant model: OR = 0.67, p = 0.015; recessive model: OR 0.57, p = 0.021; additive model: OR = 0.71, p = 0.004) after adjusting for age, gender, and the apolipoprotein E (APOE) ε4 status. Our results support the evidence that genetic variants of IL-33 affect susceptibility to LOAD in Han Chinese.

Blood Clusterin Levels, rs9331888 Polymorphism, and the Risk of Alzheimer's Disease

Variants in the clusterin gene have been associated with Alzheimers disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Anticonvulsant effect of unilateral anterior thalamic high frequency electrical stimulation on amygdala-kindled seizures in rat

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. In this study, we examined the effect of unilateral high frequency stimulation (HFS) of the ANT on amygdala-kindled seizures in Wistar rats. When fully-kindled seizures were achieved by daily amygdala kindling, HFS (15 min train of 100 μs pulses at 200 Hz and 450-800 μA) was delivered to the ipsilateral or contralateral ANT immediately before the kindling stimulation for 15 days. HFS of the ipsilateral ANT significantly decreased the incidence of generalized seizures and the mean behavioral seizure stage and afterdischarge duration (ADD), and shortened cumulative ADD and cumulative generalized seizure duration. Furthermore, HFS of the ipsilateral ANT significantly increased the afterdischarge threshold (ADT). Our data suggest that unilateral HFS of the ANT may be an effective method of inhibiting kindled seizures by suppressing the susceptibility to seizures and generating long lasting anti-epileptic effect preventing the recurrence of kindled seizures, providing an alternative to bilateral ANT DBS for refractory epilepsy.

Mitochondrial transcription factor A (TFAM) polymorphisms and risk of late-onset Alzheimer's disease in Han Chinese

Chronic mitochondria DNA (mtDNA) damage and mitochondrial dysfunction induced by increased reactive oxygen species (ROS) have been proved to contribute to the development of Alzheimers disease (AD). Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mtDNA integrity. Recently, some studies suggested two single nucleotide polymorphisms (SNPs) (rs1937 and rs2306604) in the TFAM gene are associated with sporadic late-onset AD (LOAD) in Caucasians. To explore the correlation between TFAM gene and LOAD, we performed a case-control study in a large Chinese cohort consisting of 394 patients and 390 healthy controls. The results showed that there were significant differences in genotype (P=0.03) and allele (P=0.04) frequencies of the SNP rs1937 between LOAD patients and controls. The minor C allele of rs1937 acted as a moderate protective factor of LOAD (P=0.04, odds ratios/OR=0.76). The logistic regression analysis also suggested an association of LOAD with SNP rs1937 (dominant model: P=0.03, OR=0.71; recessive model: P=0.02, OR=0.25; additive model: P=0.01, OR=0.68). No significant association was observed between rs2306604 and LOAD. Haplotype analysis identified the haplotype CC as a protective factor of LOAD (P=0.038, OR=0.76). This study provides the evidence that variations in TFAM are involved in the pathogenesis of sporadic LOAD in the Han Chinese population.

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimers disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles (P<0.001; odds ratio (OR)=2.32; 95% confidence interval (CI)=1.57-3.42) and fewer L alleles (P=0.02; OR=0.66; 95% CI=0.46-0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR=2.05, 95% CI=1.26-3.34), and this association was influenced by the presence of APOE ɛ4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.