Association of BACE1 gene polymorphism with Alzheimer's disease in Asian populations: meta-analysis including Korean samples.

BACKGROUND: Beta-site amyloid precursor protein cleaving enzyme (BACE) is a candidate risk factor for Alzheimer's disease (AD) from its key role in beta-amyloid generation. Previous genetic association studies of BACE1 gene have yielded conflicting results. This study is an attempt to clarify whether the common SNP in exon 5 of BACE1 (rs638405, Val262) is associated with a risk for late-onset AD. METHODS: We genotyped a synonymous C/G polymorphism of BACE1 located in exon 5 and apolipoprotein E (ApoE) in 248 AD patients and 224 healthy persons. A meta-analysis with pooled data from four Chinese studies and our results was performed. RESULTS: The allele and genotype frequencies of BACE1 polymorphism were not significantly different between cases and controls (p > 0.05) in the Korean population. A meta-analysis of previously published Asian populations including Koreans showed evidence of a weak association (p = 0.0555 for genotypes, p = 0.0352 for alleles). However, a significant association between the CC genotype and AD was observed in the ApoE-epsilon4-positive groups (p = 0.0044, OR = 1.995; 95% CI = 1.319-3.018). CONCLUSION: These data suggest that BACE1 polymorphism in exon 5 influences risk for late-onset AD in those carrying the ApoE epsilon4 allele.

No association of prion protein gene polymorphisms with Alzheimer's disease in Korean population.

The polymorphism at codon 129 (M129V) of the human prion protein gene (PRNP) is a known risk factor for Creutzfeldt-Jakob disease (CJD) in Caucasians. There are few reports of this polymorphism's effect on memory and on the risk of Alzheimer's disease (AD). The M129V genotype distributions among Asians are very different from Caucasians. Another polymorphism, codon 219 (E219K) is not found in Caucasians. We investigated two polymorphisms of PRNP, M129V (rs1799990) and E219K (rs1800014) in 297 Korean AD patients and 217 healthy subjects. The analysis of the genotype and allele distributions showed no significant difference between the AD patients and the controls in both polymorphisms (P=0.19 genotype, P=0.51 allele for M129V; P=0.64 genotype, P=0.50 allele for E219K). Also, the PRNP polymorphisms were not significantly associated with AD when the populations were stratified for the presence or absence of apolipoprotein E-epsilon4 (ApoE-epsilon4) allele. These results suggest that the PRNP genetic variants are not associated with the risk for AD in Korean population.

ApoE-epsilon 4-dependent association of the choline acetyltransferase gene polymorphisms (2384G>A and 1882G>A) with Alzheimer's disease.

BACKGROUND: One of the characteristic features of Alzheimer's disease (AD) is the degeneration of the cholinergic system. The gene encoding choline acetyltransferase (ChAT), a key enzyme in cholinergic function, is a candidate gene conferring risk for AD. But the genetic association of the enzyme with AD has been controversial. We analyzed 2 ChAT single nucleotide polymorphisms (SNPs), 2384G>A (rs3810950; Ala120Thr) and 1882G>A (rs1880676; Asp7Asn) and the ApoE polymorphisms in Korean population. METHODS: The samples from 316 AD patients and 264 age-matched healthy controls were analyzed. The differences in genotype frequencies were assessed. RESULTS: The 2 ChAT SNPs were almost completely linked with each other (r2=0.99, |D'|=1.0). No significant difference in the ChAT genotype distribution was observed between the patients and the controls. However, in non-ApoE-epsilon4 allele carriers, multiple logistic regression analysis showed that both the GA and the GA/AA genotypes were associated with AD (OR=1.639, 95% CI, 1.050-2.559, p=0.0297 for GA; OR=1.630, 95% CI, 1.049-2.532, p=0.0297 for GA/AA), suggesting a dominant effect of A allele. CONCLUSION: There is considerable effect of the ChAT polymorphisms on AD in Korean population and this effect is dependent on ApoE genotypes.

Serum Homocysteine and Folate Levels are Associated With Late-life Dementia in a Korean Population.

OBJECTIVES: We aimed to determine whether serum levels of homocysteine (Hcy) and its biological determinants, folate and vitamin B12, are related to cognitive decline in elderly people. METHODS: The concentrations of total Hcy, folate, and vitamin B12 were measured in serum samples from 424 cognitively normal controls, 382 mild cognitive impairment patients, and 56 dementia patients from Ansan Geriatric cohort. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was used to evaluate cognitive functions. RESULTS: The dementia patients had higher serum Hcy (dementia, 17.6 ± 6.9 µmol/L; control, 12.9 ± 5.0 µmol/L; p < 0.001) and lower serum folate (dementia, 7.9 ± 4.8 ng/mL; control, 10.0 ± 7.1 ng/mL; p = 0.034) levels compared with controls. There was an inverse relationship between Hcy levels and serum folate or vitamin B12 concentrations. The cognitive status as measured by the (CERAD) score was inversely related to Hcy levels. The adjusted odds ratio of dementia was 5.18 (95% confidence interval: 1.91-14.10; p = 0.001) for moderate (30 ≥ Hcy > 15) hyperhomocysteinemia compared with normal Hcy levels (≤15 µmol/L). In addition, there was weak association between low serum folate (<3.0 ng/mL) and the risk for dementia (crude odds ratio = 3.68; 95% confidence interval: 1.07-12.69; p = 0.039). CONCLUSION: Elevated serum Hcy and decreased serum folate concentrations are associated with the risk of dementia in Korean elders.

An aminopeptidase from Streptomyces sp. KK565 degrades beta amyloid monomers, oligomers and fibrils.

The accumulation of beta amyloid (Aß) has been a primary target for Alzheimer disease therapeutic strategies. Previously, we discovered an activity from Streptomyces sp. KK565 growth media that inhibits Aß aggregation. The active component was an aminopeptidase and named Streptomyces sp. KK565 aminopeptidase (SKAP). SKAP cleaved N-terminal amino-acids of Aß(1-42) monomer, inhibited formation of fibrils and protected Aß(1-42)-induced neurotoxicity. Over-expression of a human homolog of SKAP, glutamate carboxypeptidase II (hGCPII) in Aß-oversynthesizing cells dramatically reduced the Aß levels. These findings suggest a possible role of M28 family peptidases in preventing Aß deposits in mammalian brain.

Obesity and depressive symptoms in elderly Koreans: evidence for the "Jolly Fat" hypothesis from the Ansan Geriatric (AGE) Study.

The current study is to examine the association between obesity and depressive symptoms and to test the validity of "Jolly Fat" hypothesis in elderly Koreans. A total of 1229 elderly (60-85 years old) Koreans selected from the Ansan Geriatric Study participated in this study. Body mass index (BMI) was calculated from the measured weights and heights of subjects. Overweight and obese were defined as BMI > or =23 and > or =25, respectively. Depressive symptoms were measured using the 30-item Korean version of the Geriatric Depression Scale (K-GDS), with a cutoff point of 18. The prevalence of depressive symptoms in elderly Korean women was higher than in men (20.9% vs. 9.2%, p<0.001). Among elderly women, higher mean values of obesity indexes, such as weight, BMI, waist circumference, waist-hip ratio, and body fat mass, were found in normal subjects than in those with depressive symptoms. No such differences were found in elderly men. Obese elderly women were less likely to suffer from depressive symptoms compared to those with apparently normal weight (odds ratio (OR)=0.63, 95% CI: 0.41-0.96). This inverse association was evident after adjustment for confounders, such as age, education, personal expenses, smoking, alcohol consumption, regular exercise, self-perceived health, presence of chronic disease, and cognitive function. Our data are consistent with the "Jolly Fat" hypothesis being valid only in women, but not in men, among elderly Koreans. A causal relationship between obesity and depressive symptoms should be evaluated in future studies in elderly Korean women.

Plasma carbonic anhydrase II protein is elevated in Alzheimer's disease.

Carbonic anhydrase (CA) plays a critical role in pH regulation, long-term synaptic transformation, and is associated with mental retardation, Alzheimer's disease (AD), and Down syndrome. There is accumulating evidence that CAII is increased in AD brain. The present study focused on the determination of CAII protein level in blood plasma samples using immunoblot and ELISA methods. We compared plasma from 91 AD patients (average age 74.8 y), 83 persons with amnestic mild cognitive impairment (MCI) (average age 73.7 y), and 113 cognitively normal controls (average age 70.8 y). The plasma level of CAII was significantly increased in AD patients, as compared to control groups. CAII levels were higher in males than females. There was an age-dependent increase of CAII. These results provide further evidence that changes in CAII level may play a role in the pathogenesis of AD.

Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: a genetic association study.

Ubiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of amyloid precursor protein (APP) was reported to be associated with decreased levels of beta amyloid (Abeta) aggregates, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD). We investigated the association between genetic variations of Ubc9 gene (UBE2I) and late-onset Alzheimer's disease (AD). Five single nucleotide polymorphisms (SNPs) in UBE2I were genotyped in the DNA samples of 312 AD patients, 347 subjects with mild cognitive impairment (MCI), and 489 cognitively healthy controls. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE-epsilon4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. Our investigation suggests that UBE2I polymorphisms might be associated with a risk of AD and MCI.

Nicotinamide reduces dopamine in postnatal hypothalamus and causes dopamine-deficient phenotype.

Dopamine is an important neurotransmitter in the human central nervous system and also plays a key role in the development of postnatal brains. We previously reported that nicotinamide, a SIRT1 inhibitor, regulates tyrosine hydroxylase (TH) expression in vitro. To investigate the effect of nicotinamide-mediated TH regulation in vivo, nicotinamide was chronically injected into neonatal mice. Interestingly, nicotinamide-treated mice were smaller in size, and their locomotor activity was reduced. L-DOPA treatment caused hypersensitive locomotor activity that indicates a dopamine-depleted state. These changes seemed to be associated with dopamine metabolism in hypothalamus, since dopamine in hypothalamus was reduced but not in striatum. The present study suggests that the regulation of dopamine metabolism during the postnatal development is important and the underlying molecular mechanisms may be associated with SIRT1 signaling.

SIRT1 regulates tyrosine hydroxylase expression and differentiation of neuroblastoma cells via FOXO3a.

To examine the function of SIRT1 in neuronal differentiation, we employed all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. Nicotinamide inhibited neurite outgrowth and tyrosine hydroxylase (TH) expression. Inhibition of PARP or histone deacetylase did not inhibit TH expression, showing the effect to be SIRT1 specific. Expression of FOXO3a and its target proteins were increased during the differentiation and reduced by nicotinamide. FOXO3a deacetylation was increased by ATRA and blocked by nicotinamide. SIRT1 and FOXO3a siRNA inhibited ATRA-induced up-regulation of TH and differentiation. Taken together, these results indicate that SIRT1 is involved in ATRA-induced differentiation of neuroblastoma cells via FOXO3a.