alpha 1-Antichymotrypsin as a risk modifier for late-onset Alzheimer's disease in Japanese apolipoprotein E epsilon 4 allele carriers.

In the Japanese population, sporadic late-onset Alzheimer's disease (LOAD) cases had significantly higher frequencies of the A allele of alpha 1-antichymotrypsin (ACT) gene as well as the epsilon 4 allele of apolipoprotein E (APOE) gene than controls. The odds ratio for LOAD in APOE4 carriers with the ACT-A allele was more than six times that in APOE4 carriers without the ACT-A allele (21.1 vs 3.2). These results indicate that the ACT-A allele is a risk modifier for LOAD in APOE4 carriers.

T/G polymorphism at intron 9 of presenilin 1 gene is associated with, but not responsible for sporadic late-onset Alzheimer's disease in Japanese population.

To investigate whether presenilin 1 (PS1) gene, a major causative gene of familial early-onset Alzheimer's disease (AD), also contributes to the etiology of sporadic AD, we evaluated associations between Japanese AD and polymorphisms located at 14q24.3. While the D14S43 and FOS loci showed no association with either early- or late-onset AD, late-onset AD carrying no APOE-epsilon4 allele was associated with the G allele of the T/G polymorphism located at intron 9 of the PS1 gene (P = 0.016). Considering another study showing a positive association between AD and the T allele, this polymorphism is associated with, but not responsible for sporadic late-onset Alzheimer's disease.

Elevated amyloid beta protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells.

The deposition of amyloid beta protein (A beta) in the cerebral cortex is the pathological characteristic of Alzheimer's disease (AD), and patients with AD suffer from progressive memory loss. Transgenic experiments have revealed that long-term memory is dependent on cyclic AMP-response element binding protein, CREB. CREB phosphorylation at serine-133 is essential for its transcriptional activity. Here we demonstrated that A beta(1-40), at a concentration more than 1 microM, induced CREB phosphorylation at serine-133 in rat pheochromocytoma PC12 cells. A beta(1-40) induced phosphorylation of p44 and p42 MAP kinases (Erk1 and Erk2) at tyrosine-204, and PD98059, a MEK1 inhibitor, inhibited A beta(1-40)-induced CREB phosphorylation at serine-133. We conclude that elevated A beta(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase-dependent pathway.

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 Alzheimer's 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.

Mutational screening of APP gene in patients with early-onset Alzheimer disease utilizing mismatched PCR-RFLP.

To elucidate the frequency of mutations of the beta/A4 amyloid protein precursor (APP) gene in early-onset Alzheimer disease, we designed a mismatched PCR-RFLP that can identify all kinds of missense mutations at codon 717 in addition to the seven kinds of known mutations at exon 17. When we screened mutations at exon 17 utilizing this method and the double missense mutations at exon 16 of the APP gene by PCR-RFLP, no cases revealed mutations of the APP gene among 13 familial and 54 sporadic cases, except one family (OS-1) that had previously been reported and used as a positive control of APP717(Val-->Ile). Our results support the hypothesis that mutations in the APP gene are not major causes in early-onset Alzheimer disease.

Genetic association study between senile dementia of Alzheimer's type and APOE/C1/C2 gene cluster.

Senile dementia of Alzheimer's type (SDAT) is characterized by progressive deficits of multiple cognitive functions in elderly more than 65 years of age. The APOE-epsilon 4 allele has been shown to be a risk factor for SDAT. To investigate the genetic interactions between SDAT and the APOE/APOC1/APOC2 gene cluster located at 19q13.2, we genotyped these genes in patients with SDAT and nondemented controls. Although allelic associations were found between the APOC1 locus and SDAT (p = 0.0022) as well as between the APOE locus and SDAT (p < 0.0001), no associations were detected between the APOC2 locus and SDAT. And the association between the APOE and APOC1 locus in SDAT was statistically more significant than that in controls (p < 0.001). Estimation of the haplotype frequencies indicated that the association between the APOE/APOC1 haplotype and SDAT was more significant than linkage disequilibrium between the APOE and APOC1 locus (p < 0.01). These results suggest that genetic interaction between the APOE and APOC1 gene could modify a risk factor of APOE-epsilon 4 for SDAT. The APOE/APOC1 locus was estimated to be responsible for 54.8% of SDAT in the Japanese population.

[Familial Alzheimer's disease in Japanese population].

We ascertained 56 related cases with early onset familial Alzheimer's disease (EOFAD; mean age of onset < 65 years) and 10 related cases with late onset familial Alzheimer's disease (LOFAD; mean age of onset > or = 65 years) through a questionnaire administered to neuro-psychiatric and medical school hospitals in Japan and through a review of cases in Japanese literature. Mean age of onset and death (+/- S.D.) of EOFAD were 43.4 +/- 8.6 years (n = 94) and 51.1 +/- 10.5 years (n = 85), respectively. Distributions of the age-onset were relatively constant within a family but significantly different between families. Our result may suggest that clinical differences between families represent genetic heterogeneity at the molecular level. Six out of 32 related cases of with EOFAD showed the 717 Val-->Ile mutation of beta/A4 amyloid precursor protein (APP) gene. This result suggests that the frequency of this mutation in Japanese population is higher than in Caucasian and allelic the existenced heterogeneity, in Japanese EOFAD.

[A case of Hashimoto's thyroiditis associated with renal tubular acidosis, Sjögren syndrome and empty sella syndrome].

This report describes a 48-year old female patient with Hashimoto's thyroiditis, distal-type renal tubular acidosis (d-RTA), Sjögren syndrome (SjS), and empty sella syndrome (ESS). She has been receiving replacement of thyroxine for Hashimoto's thyroiditis since 1967. She felt muscle weakness and numbness in the extremities and was found to have low serum potassium (2.9 mEq/l) in 1987. Since then she has been administrated potassium chloride orally. She was admitted to our hospital because of recurrence of muscle weakness and numbness of the extremities in November 1990. Laboratory examination revealed that her serum levels of antimicrosomal antibody and anti-thyroglobulin antibody were highly positive (MCHA: x 2(10) x 100, and TGHA: x 100). Furthermore, she was revealed to have 1) d-RTA by oral tolerance tests with the administration of NH4Cl and NaHCO3, 2) SjS by Schirmer test and sialography, and 3) ESS by computed tomography and magnetic resonance imaging examinations of the pituitary. Association of Hashimoto's thyroiditis, d-RTA, SjS and ESS in this case may possibly be caused by common autoimmune mechanism.