Kouzin Kamino

Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia

Although dementia of the Alzheimers type (DAT) is the most common form of dementia, the severity of dementia is only weakly correlated with DAT pathology. In contrast, postmortem measurements of cholinergic function and membrane ethanolamine plasmalogen (PlsEtn) content in the cortex and hippocampus correlate with the severity of dementia in DAT. Currently, the largest risk factor for DAT is age. Because the synthesis of PlsEtn occurs via a single nonredundant peroxisomal pathway that has been shown to decrease with age and PlsEtn is decreased in the DAT brain, we investigated potential relationships between serum PlsEtn levels, dementia severity, and DAT pathology. In total, serum PlsEtn levels were measured in five independent population collections comprising >400 clinically demented and >350 nondemented subjects. Circulating PlsEtn levels were observed to be significantly decreased in serum from clinically and pathologically diagnosed DAT subjects at all stages of dementia, and the severity of this decrease correlated with the severity of dementia. Furthermore, a linear regression model predicted that serum PlsEtn levels decrease years before clinical symptoms. The putative roles that PlsEtn biochemistry play in the etiology of cholinergic degeneration, amyloid accumulation, and dementia are discussed.

Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population

The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.

Regulation of Notch Signaling by Dynamic Changes in the Precision of S3 Cleavage of Notch-1†

ABSTRACT Intramembrane proteolysis by presenilin-dependent γ-secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-β. Here, we show that upon Notch signaling the intracellular domain of Notch-1 is cleaved into two distinct types of NICD species due to diversity in the site of S3 cleavage. Consistent with the N-end rule, the S3-V cleavage produces stable NICD with Val at the N terminus, whereas the S3-S/S3-L cleavage generates unstable NICD with Ser/Leu at the N terminus. Moreover, intracellular Notch signal transmission with unstable NICDs is much weaker than that with stable NICD. Importantly, the extent of endocytosis in target cells affects the relative production ratio of the two types of NICD, which changes in parallel with Notch signaling. Surprisingly, substantial amounts of unstable NICD species are generated from the Val→Gly and the Lys→Arg mutants, which have been reported to decrease S3 cleavage efficiency in cultured cells. Thus, we suggest that the existence of two distinct types of NICD points to a novel aspect of the intracellular signaling and that changes in the precision of S3 cleavage play an important role in the process of conversion from extracellular to intracellular Notch signaling.

Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families

Presenilin-1 (PS-1) gene of three Japanese pedigrees with early-onset familial Alzheimers disease (FAD) disclosed two novel missense mutations resulting in Val96Phe and Ile213Thr, and one mutation resulting in His163Arg. The mean age at onset in a family with His163Arg mutation was similar to those reported in other families with His163Arg. Our results suggested the existence of a variety of PS-1 mutations, and that early-onset FAD with PS-1 mutations is highly penetrant and is only rarely subject to modulation by genetic or environmental modifying factors.

Genetic deficiency of a mitochondrial aldehyde dehydrogenase increases serum lipid peroxides in community-dwelling females

AbstractMitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We and others have previously reported that such a deficiency influences the risk for late-onset Alzheimers disease (LOAD), hypertension, and myocardial infarction. Then we tried to find phenotypes to which the ALDH2 polymorphism contributes by conducting several evaluations including biochemical and functional analyses of various tissues in a community-dwelling population. Several serum proteins, lipids, and lipid peroxides (LPO) levels showed differences between the nondefective (ALDH2*1/1) and defective (ALDH2*1/2 and ALDH2*2/2) ALDH2 individuals. However, alcohol-drinking behavior is known to affect these evaluations. Thus, we excluded the effects of alcohol-drinking behavior from the association with the ALDH2-deficient genotype through correction and found that the concentration of LPO was significantly lower in the nondefective ALDH2 females than the defective females. The effect of frequent alcohol-drinking behavior in males seems to override the phenotype of the high serum LPO level. These results indicate that the ALDH2 deficiency may enhance oxidative stress in vivo. Thus, these findings suggest that ALDH2 functions as a protector against oxidative stress and the decrease in protection may influence the onset of AD, hypertension, and myocardial infarction.

Variations in the BDNF Gene in Autopsy-Confirmed Alzheimer’s Disease and Dementia with Lewy Bodies in Japan

Background/Aim: Brain-derived neurotrophic factor (BDNF) is associated with the hippocampus and the nigrostriatal dopaminergic function. Data showing that its level was reduced in Alzheimer’s disease (AD) and Parkinson’s disease (PD) suggested that the BDNF function must play an important role in the pathogenetics of these diseases. Indeed, variation in the BDNF gene may confer susceptibility to AD and PD development. Recently, a functional BDNF Val66Met polymorphism has been found to be associated with episodic memory and hippocampal function, with intracellular trafficking, and with activity-dependent secretion of BDNF. To date, there have been several conflicting reports on the correlation between AD or PD and Val66Met or C270T polymorphism in the BDNF promoter region, although no data on this relationship have been published with respect to dementia with Lewy bodies (DLB). In the present study, we investigated a possible association between such BDNF polymorphisms and susceptibility to AD or DLB. Methods:BDNF genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism method in autopsy-confirmed human samples. Results and Conclusion: On comparing patients and controls, the distribution of BDNF genotypes and alleles did not differ significantly. Our findings suggest that it is unlikely that these BDNF polymorphisms play a major role in the pathogenesis of AD and DLB in the Japanese population.

Polymorphism of the Apolipoprotein E and Angiotensin-Converting Enzyme Genes in Japanese Subjects With Silent Myocardial Ischemia

The apolipoprotein epsilon4 allele and homozygous deletion allele (DD) of the angiotensin-converting enzyme gene are reported to be associated with an increase in the incidence of ischemic heart disease. In this study, we examined whether the apolipoprotein epsilon4 genotype and angiotensin-converting enzyme/DD allele are associated with silent myocardial ischemia. We screened 3920 subjects undergoing general checkups who no symptoms of ischemic heart disease. Seventy subjects (2 percent) showed ischemic ST-segment depression during the double two-step exercise test. One hundred and twenty control subjects without ischemic ST-segment depression were recruited from the same population and matched for sex, age, and blood pressure. We performed genotyping of the apolipoprotein E gene (epsilon2, epsilon3, and epsilon4) and angiotensin-converting enzyme gene (I and D) using polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction, respectively. Allele frequently of epsilon4 of the apolipoprotein E gene was higher in the ischemic group (11 percent) than the nonischemic group (5 percent) (chi2 = 5.35, P < .05), but there was no significant association between the allele or the genotype frequency of the angiotensin-converting enzyme gene and the incidence of ischemic ST-segment depression. Furthermore, stepwise multiple regression analysis also revealed that total cholesterol level and epsilon4 genotype were predictors of ischemic change in the exercise tolerance test (chi2 = 12.8, P < .005, R(2) = .051). These results suggest that the apolipoprotein epsilon4 allele is an independent genetic risk factor for silent myocardial ischemia in Japanese subjects.

Identification of hippocampus‐related candidate genes for Alzheimer's disease

Alzheimers disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. We performed an association study using 376 AD patients and 376 control subjects. We studied 35 single nucleotide polymorphisms in 35 genes that were significantly downregulated or upregulated only in the AD hippocampus compared with control and found that 9 single nucleotide polymorphisms were associated with AD. Our data indicated that single nucleotide polymorphisms could highly reflect differences in gene expression. Furthermore, an intronic polymorphism (+9943T/C) in POU2F1 was most significantly associated with AD (p = 0.0007). Our results suggest that POU2F1 is a candidate gene for AD. Ann Neurol 2005;57:585–588

The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex

Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio=1.12, p=0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p<0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p=0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC.

Association study of KIBRA gene with memory performance in a Japanese population

Abstract Objectives. Papassotiropoulos et al. (Science 314: p 475) discovered that a single nucleotide polymorphism (SNP) of the KIBRA gene (rs17070145) was associated with delayed recall performance in Caucasians. KIBRA is highly expressed in the brain and kidneys, and is reported to be involved in synaptic plasticity. Therefore, we first tried to replicate the association between the SNP and memory performance in a Japanese subjects. Methods. We examined the association between the SNP and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) in 187 healthy Japanese people. Results. The T allele carriers had significantly better verbal memory, attention/concentration and delayed recall performance than the C/C carriers (corrected P = 0.044, 0.047 and 0.0084, respectively). Furthermore, the C/T carriers and the T/T carriers had better delayed recall performance than the C/C carriers (post hoc P = 0.0017 and 0.0096). Conclusions. This data suggest that the C/C genotype might have an impact on memory performance in Asian populations as well as in Caucasian populations. Further investigation to clarify the association of the KIBRA gene with memory in other ethnic groups is warranted.