Dan Miao

Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer's disease

Pro- and anti-inflammatory cytokines play an important role in Alzheimers disease (AD), and common polymorphisms of genes controlling their production have been shown to be associated with the susceptibility to sporadic AD. Interleukin (IL)-18 is a potent pro-inflammatory cytokine of the IL-1 superfamily, and increasing evidences indicate a crucial role for it in the pathogenesis of AD. To clarify the role of IL-18 as a potential cause for AD susceptibility, we investigated the effect of two functional polymorphisms in IL-18 promoter: -607 C/A (rs1946518) and -137 G/C (rs187238) for the risk of sporadic late onset Alzheimers disease (LOAD) in a Han Chinese population of 109 patients and 109 healthy controls matched for sex and age. All 218 subjects were also genotyped for the Apolipoprotein E (ApoE) polymorphisms. The results revealed that both -607 C allele and -137 G allele were associated with an increased risk of LOAD (odds ratios/OR=1.56, P=0.04, Power=0.96 and OR=1.85, P=0.03, Power=0.80, respectively), and these associations were influenced by the presence of ApoE epsilon4 alleles. Moreover, they showed a highly significant synergistical interaction with the ApoE epsilon4 allele (OR=5.70 and 4.64, respectively). Examination of the haplotypes identified the -607 C/-137 G haplotype to increase the risk of LOAD (OR=1.62, P=0.003, Power=0.97). These findings suggest that the functional polymorphisms in IL-18 promoter may be involved in the risk of developing sporadic LOAD in the Han Chinese population.

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.

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.

Blocking β2-adrenergic receptor attenuates acute stress-induced amyloid β peptides production

Environmental factors play an important role in the Alzheimers disease (AD) development and stress may accelerate the progression of AD. Beta-adrenergic receptors are activated by stress and may influence different aspects of cognitive function. So, it was hypothesized that stress may accelerate the pathological progression of AD by the activation of beta(2)-adrenergic receptor (beta(2)-AR). We have investigated the role of acute stress and activation of beta(2)-AR in amyloid beta (Abeta) peptides production in a mouse model of acute restraint stress. Injections of the beta(2)-AR-selective agonist clenbuterol hydrochloride enhanced the production of acute stress-induced Abeta peptides production; the beta(2)-AR-selective antagonist ICI 118,551 reduced Abeta peptides production. It is suggested that acute stress induces abnormal activation of beta(2)-AR which subsequently enhances Abeta peptides (the main neuropathological hallmarks of AD) production possibly resulting in the onset of AD. The findings indicate that new therapeutic strategies designed to blocking beta(2)-AR might be valuable for the prevention and treatment of AD.

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.

Genetic association of TLR4/11367 polymorphism with late-onset Alzheimer's disease in a Han Chinese population

The amyloid beta-protein (A-β) 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 4 (TLR4) is thought to contribute to Aβ clearance. Studies have reported the presence and functional significance of the TLR4/11367 polymorphism in a Han Chinese population. To evaluate the involvement of the TLR4/11367 polymorphism in the risk of late-onset Alzheimers disease (LOAD), we performed a case-control study to analyze the genotype and allele distributions of the TLR4/11367 polymorphism in a Han Chinese population (137 LOAD cases and 137 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P<0.001, allele P<0.001). After stratification by APOE ε4-carrying status, the C allele of the TLR4/11367 polymorphism was still significantly associated with LOAD in APOE ε4 non-carriers (OR=5.77, 95% CI=3.03-11.00, P<0.001) and carriers (OR=2.03, 95% CI=1.03-3.98, P=0.04). In addition, a logistic regression analysis also conferred positive association between TLR4/11367C and LOAD (dominant model: ORa=3.08, 95% CI=1.60-5.93, P=0.001; recessive model: ORa=8.79, 95% CI=3.31-23.36, P<0.001; additive model: ORa=2.75, 95% CI=1.73-4.37, P<0.001) after adjustment for age, gender, and the APOE ε4 carrier status. This study gives the first evidence that the TLR4/11367 polymorphism was associated with LOAD in a Han Chinese population.

Interleukin-18 promoter polymorphisms and risk of ischemic stroke

Ischemic stroke (IS) is a major cause of morbidity and mortality around the world. Interleukin-18 (IL-18) plays an important role in the pathogenesis of IS and IL-18 promoter polymorphisms have been shown to be associated with levels of expression of IL-18. We investigated the association of two functional polymorphisms in IL-18 promoter, -607C/A (rs1946518) and -137G/C (rs187238), with the risk of ischemic stroke in a Han Chinese population of 423 patients and 384 healthy controls matched for sex and age. The results revealed that the -607C allele was associated with an increased risk of IS with an odds ratios (OR) of 1.358 (P = 0.002, power = 100%) and the presence of the -137G allele was correlated with increased the risk of IS in the subtype of patients with large artery atherosclerosis (LAA) (OR = 1.583, P = 0.02, power = 94%). Patients with the -607C/-137G haplotype also had significantly increased risk of IS compared to controls (OR = 1.341, P = 0.005, power = 100%). Our findings suggest that these functional polymorphisms in the IL-18 promoter are involved in development of IS in the Han Chinese population.

An exploratory study on STX6, MOBP, MAPT, and EIF2AK3 and late-onset Alzheimer's disease.

Both Alzheimers disease (AD) and progressive supranuclear palsy (PSP) are a class of neurodegenerative diseases associated with the pathologic aggregation of tau protein in the human brain. They share some clinical and pathologic characteristics. A recent genome-wide association study reported several single-nucleotide polymorphisms at the STX6, MOBP, MAPT, and EIF2AK3 in association with PSP. To explore whether these single-nucleotide polymorphisms are associated with AD risk, we conducted a case-control study to investigate the PSP-associated loci in 1592 Han Chinese subjects. Rs242557 at the MAPT locus was associated with late-onset AD (LOAD) (odds ratio [OR], 1.175; p = 0.026), which appeared to be stronger for LOAD patients with apolipoprotein E (APOE) ε4 allele (OR, 1.510), and this positive association was not changed after adjusting for age, sex, and the APOE ε4-carrier status (additive model: OR, 1.163; p = 0.036; dominant model: OR, 1.315; p = 0.010). Rs1768208 in MOBP and rs7571971 in EIF2AK3 showed association only in the APOE ε4 positive subjects, and these did not appear to be independent of APOE. As for rs1411478 in STX6, we did not explore any association with LOAD. Our exploratory analysis mainly suggests an association of MAPT with LOAD, especially in APOE ε4 carriers. Genotypes at MOBP and EIF2AK3 confer risk predominantly in APOE ε4-positive subjects, with indications of an interaction between APOE and MOBP or EIF2AK3 on AD risk.Both Alzheimers disease (AD) and progressive supranuclear palsy (PSP) are a class of neurodegenerative diseases associated with the pathologic aggregation of tau protein in the human brain. They share some clinical and pathologic characteristics. A recent genome-wide association study reported several single-nucleotide polymorphisms at the STX6, MOBP, MAPT, and EIF2AK3 in association with PSP. To explore whether these single-nucleotide polymorphisms are associated with AD risk, we conducted a case-control study to investigate the PSP-associated loci in 1592 Han Chinese subjects. Rs242557 at the MAPT locus was associated with late-onset AD (LOAD) (odds ratio [OR], 1.175; p = 0.026), which appeared to be stronger for LOAD patients with apolipoprotein E (APOE) ε4 allele (OR, 1.510), and this positive association was not changed after adjusting for age, sex, and the APOE ε4-carrier status (additive model: OR, 1.163; p = 0.036; dominant model: OR, 1.315; p = 0.010). Rs1768208 in MOBP and rs7571971 in EIF2AK3 showed association only in the APOE ε4 positive subjects, and these did not appear to be independent of APOE. As for rs1411478 in STX6, we did not explore any association with LOAD. Our exploratory analysis mainly suggests an association of MAPT with LOAD, especially in APOE ε4 carriers. Genotypes at MOBP and EIF2AK3 confer risk predominantly in APOE ε4-positive subjects, with indications of an interaction between APOE and MOBP or EIF2AK3 on AD risk.

SIRT2 polymorphism rs10410544 is associated with Alzheimer's disease in a Han Chinese population

Sirtuin 2 (SIRT2) is a strong protein deacetylase, which is highly expressed in central nervous system. Recently, an association between SIRT2 rs10410544 polymorphism and late-onset Alzheimers disease (LOAD) was found in the APOEε4-negative Caucasian population. To investigate the potential association between the rs10410544 C/T polymorphism of SIRT2 and the risk of LOAD, we conducted an independent replication case-control study in a Northern Han Chinese population comprising 1133 cases and 1159 healthy controls being matched for age and gender. The results revealed that there were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.008, allele P=0.009). When compared with the C allele, the T allele of rs10410544 demonstrated a 1.709-fold risk for developing LOAD. After stratification by apolipoprotein E (APOE) ε4-carrying status, only APOEε4 noncarriers (P=0.035, adjusted OR=1.656, 95% CI: 1.036-2.647) showed the relation between LOAD and SIRT2 rs10410544 T allele. This study provides the evidence that the rs10410544 C/T polymorphism of SIRT2 was associated with genetic susceptibility to LOAD in a Northern Han Chinese population.

Lack of association between rs597668 polymorphism near EXOC3L2 and late-onset Alzheimer's disease in Han Chinese.

Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimers disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P=0.653; allele: P=0.603), even after stratification for apolipoprotein E (APOE) ɛ4 status and statistical adjustment for age, gender and APOE ɛ4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population.