RESUMEN

Type 5 17ß-hydroxysteroid dehydrogenase (17ß-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17ß-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5α-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17ß-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17ß-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (HTS) and identified compound 2, which displayed a structure distinct from known 17ß-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties.

Asunto(s)

3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Indoles/química , Piperidinas/química , 3-Hidroxiesteroide Deshidrogenasas/genética , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Administración Oral , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Células HEK293 , Semivida , Humanos , Hidroxiprostaglandina Deshidrogenasas/genética , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Indoles/farmacocinética , Indoles/uso terapéutico , Masculino , Ratones , Ratones Desnudos , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Testosterona/metabolismo , Trasplante Heterólogo

RESUMEN

OBJECTIVE: presenilin-2 is one of the causative genes for familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor for late-onset and sporadic early-onset Alzheimer's disease. Polymorphism of the regulatory region of presenilin-2 has recently been reported to be associated with sporadic Alzheimer's disease in a Russian population. The purpose of this study was to determine whether Alzheimer's disease is associated with the presenilin-2 gene polymorphism and the apolipoprotein E genotype in an extended case-control study. METHODS: We examined 230 patients with Alzheimer's disease, along with an equal number of age- and sex-matched controls from the same community, in a Japanese population by using a Chi-square test for homogeneity and a logistic regression analysis. RESULTS: The presenilin-2 polymorphism frequencies were similar in early-onset Alzheimer's disease patients (0.17) and younger controls (0.15), and in late-onset Alzheimer's disease (0.20) and elderly controls (0.20). We found no evidence for an association between the presenilin-2 polymorphism and the apolipoprotein E epsilon4 allele. CONCLUSIONS: Our results fail to support an association of presenilin-2 gene polymorphism with Alzheimer's disease. The discrepancy between our results and the results of the Russian study appear to be due to racial differences.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Polimorfismo Genético , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Apolipoproteína E4 , Apolipoproteínas E/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Intervalos de Confianza , Análisis Mutacional de ADN/métodos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Presenilina-2 , Secuencias Reguladoras de Ácidos Nucleicos/genética , Estudios Retrospectivos

RESUMEN

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17. Clinical variability is seen not only among families with different mutations, but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia and parkinsonism family. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and it preceded dementia. Three autopsied cases shared involvement predominantly in the frontal and temporal lobes and also in the subcortical nuclei, including substantia nigra, globus pallidus, and subthalamic nucleus, that microscopically consisted of neuronal loss, microvacuolation, and astrocytic fibrosis. Immunohistochemistry demonstrated neuropil threads, ballooned cells, and glial fibrillary tangles. Sequencing analysis of the MAPT gene showed an alteration in one allele, resulting in a P301S substitution. These findings suggest that the MAPT P301S mutation can cause pathologically subcortical-predominant, neuropil thread-rich, tau-containing lesions, which could result in consistent parkinsonism. Our study confirms the notion that the phenotype observed in affected individuals from P301S MAPT mutation families is heterogeneous and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations.

Asunto(s)

Demencia/genética , Heterogeneidad Genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Mutación Puntual , Adulto , Ganglios Basales/patología , Cerebelo/patología , Demencia/patología , Corteza Entorrinal/patología , Salud de la Familia , Femenino , Hipocampo/patología , Humanos , Masculino , Enfermedad de Parkinson/patología , Linaje , Fenotipo , Proteínas tau

Asunto(s)

Enfermedad de Alzheimer , Cuerpos de Inclusión/patología , Enfermedad de Pick/metabolismo , Proteínas tau/metabolismo , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Corteza Cerebral/patología , Femenino , Humanos , Cuerpos de Inclusión/ultraestructura , Enfermedad de Pick/complicaciones , Enfermedad de Pick/patología

RESUMEN

The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.

Asunto(s)

Demencia/genética , Proteínas Asociadas a Microtúbulos/genética , Trastornos Parkinsonianos/genética , Proteínas tau/genética , Adulto , Edad de Inicio , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo

RESUMEN

OBJECTIVE: The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. METHOD: In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups. RESULTS: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. CONCLUSIONS: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Inhibidores de la Colinesterasa/uso terapéutico , Hipocampo/patología , Indanos/uso terapéutico , Piperidinas/uso terapéutico , Anciano , Apolipoproteínas E/genética , Atrofia , Inhibidores de la Colinesterasa/farmacología , Estudios de Cohortes , Progresión de la Enfermedad , Donepezilo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Genotipo , Evaluación Geriátrica , Hipocampo/efectos de los fármacos , Humanos , Indanos/farmacología , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Piperidinas/farmacología , Estudios Prospectivos , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Factores de Tiempo , Resultado del Tratamiento

Asunto(s)

Haplotipos/genética , Mutación , Fenotipo , Proteínas tau/genética , Adulto , Asparagina/genética , Femenino , Humanos , Lisina/genética , Masculino

Asunto(s)

Lóbulo Frontal , Enfermedades Neurodegenerativas , Lóbulo Frontal/patología , Humanos , Imagen por Resonancia Magnética , Degeneración Nerviosa , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/psicología , Enfermedades Neurodegenerativas/terapia , Psicotrópicos/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Síndrome , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND: Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by expansion of CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. Because the number of triplets in patients with SCA17 in previous studies ranged from 43 to 63, the normal number of trinucleotide units has been considered to be 42 or less. However, some healthy subjects in SCA17 pedigrees carry alleles with the same number of expanded repeats as patients with SCA17. OBJECTIVE: To investigate the minimum number of CAG/CAA repeats in the TBP gene that causes SCA17. DESIGN: We amplified the region of the TBP gene containing the CAG/CAA repeat by means of polymerase chain reaction and performed fragment and sequence analyses. PATIENTS: The subjects included 734 patients with SCA (480 patients with sporadic SCA and 254 patients with familial SCA) without CAG repeat expansions at the SCA1, SCA2, Machado-Joseph disease, SCA6, SCA7, or dentatorubral-pallidolluysian atrophy loci, with 162 healthy subjects, 216 patients with Parkinson disease, and 195 with Alzheimer disease as control subjects. RESULTS: Eight patients with SCA possessed an allele with more than 43 CAG/CAA repeats. Among the non-SCA groups, alleles with 43 to 45 repeats were seen in 3 healthy subjects and 2 with Parkinson disease. In 1 SCA pedigree, a patient with possible SCA17 and her healthy sister had alleles with 45 repeats. A 34-year-old man carrying alleles with 47 and 44 repeats (47/44) had developed progressive cerebellar ataxia and myoclonus at 25 years of age, and he exhibited dementia and pyramidal signs. He was the only affected person in his pedigree, although his father and mother carried alleles with mildly expanded repeats (44/36 and 47/36, respectively). In another pedigree, 1 patient carried a 43-repeat allele, whereas another patient had 2 normal alleles, indicating that the 43-repeat allele may not be pathologic in this family. CONCLUSIONS: We estimate that 44 CAG/CAA repeats is the minimum number required to cause SCA17. However, the existence of unaffected subjects with mildly expanded triplets suggests that the TBP gene mutation may not penetrate fully. Homozygosity of alleles with mildly expanded triplet repeats in the TBP gene might contribute to the pathologic phenotype.

Asunto(s)

Penetrancia , Ataxias Espinocerebelosas/genética , Proteína de Unión a TATA-Box/genética , Repeticiones de Trinucleótidos/genética , Adulto , Alelos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , ADN/genética , Cartilla de ADN , Demencia/etiología , Femenino , Ataxia de la Marcha/etiología , Ataxia de la Marcha/fisiopatología , Humanos , Masculino , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Mioclonía/etiología , Mioclonía/fisiopatología , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trastornos del Habla/etiología , Ataxias Espinocerebelosas/psicología

RESUMEN

To investigate a possible effect of the apolipoprotein (APOE) epsilon4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE epsilon3/3, epsilon3/4, or epsilon4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE epsilon4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE epsilon4 allele is related to an accelerated memory decline in AD.

Asunto(s)

Alelos , Enfermedad de Alzheimer/complicaciones , Apolipoproteínas E/genética , Trastornos de la Memoria/etiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/clasificación , Apolipoproteínas E/metabolismo , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos

RESUMEN

This study reports a novel presenilin 1 (PS1) gene mutation in a Japanese family with Alzheimer's disease (AD). Two patients developed progressive memory disorder with disorientation around 50 years of age and showed myoclonus with frequent tonic-clonic seizures several years later. Direct sequencing of the proband's PS1 gene revealed a novel mis-sense mutation (leucine-to-valine at residue 250 (L250V)). This mutation was found in both patients, but not in a normal family member or normal Japanese control subjects. Thus, L250V is a novel PS1 gene mutation responsible for familial AD (FAD) in Japan.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Mutación , Mioclonía/genética , Convulsiones/genética , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Sustitución de Aminoácidos , Apolipoproteínas E/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Electroencefalografía , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón , Masculino , Trastornos de la Memoria/etiología , Persona de Mediana Edad , Mioclonía/complicaciones , Mioclonía/diagnóstico , Linaje , Presenilina-1 , Convulsiones/complicaciones , Convulsiones/diagnóstico

RESUMEN

Since the original description of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) during the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 70 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 29 mutations outside and on exon 10 of tau gene. Here, we report the progress in clinical, genetic and pathological studies of FTDP-17 in Japan. There have been 15-separetely ascertained families described in Japan. These kindreds harbor following tau mutations: exon 10, exonic mutations, N 279 K, N 296 H, P 301 L and P 301 S; exon 10 5' splice-site mutations, S 305 N (-2), +11, and +12; exon 1, R 5 H mutation; exon 9, L 266 V mutation; and exon 13, R 406 W mutation. The phenotype of FTDP-17 kindreds varies significantly between families with different mutations and among the families carrying the same mutation. This variability is also seen in Japanese kindreds. Exon 10, P 301 L, +16 and N 279 K mutations are the most common but only P 301 L and N 279 K mutations have been described so far in Japan. On the other hand, R 5 H, N 296 H, +11, and +12 mutations have not been identified outside of Japan. Comparison of phenotypes of Japanese and non-Japanese families with P 301 S, P 301 L and R 406 W mutations uncovers significant differences in clinical presentations. It is difficult to compare pathology of Japanese and non-Japanese families on the basis of available medical literature but no apparent differences can be seen. Autopsies demonstrate the presence of neuronal and glial tau inclusions and ballooned neurons, frequently in the distribution seen in other sporadic tauopathies. A search for the common founder in Japanese families may be successfully performed. FTDP-17 families have been identified with increasing frequency in Japan. The discovery of tau mutations and the fact that they are responsible for the disease processes in the brain lead to the major advancement of our understanding of neurodegeneration. It is hoped that future studies of these families will also lead to finding the curative treatments for the tauopathies.

Asunto(s)

Cromosomas Humanos Par 17 , Demencia/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación , Trastornos Parkinsonianos/genética , Demencia/epidemiología , Exones/genética , Humanos , Japón/epidemiología , Enfermedades Neurodegenerativas/genética , Trastornos Parkinsonianos/epidemiología , Fenotipo , Parálisis Supranuclear Progresiva/genética , Proteínas tau/genética

RESUMEN

Approximately 60% of familial and sporadic Alzheimer's disease (AD) cases manifest Lewy bodies (LBs), of which a major component is alpha-synuclein. Although the pathogenic role of alpha-synuclein in AD remains unclear, LB formation might be associated with pathological beta-amyloid (Abeta) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Abeta deposition in senile plaques and amyloid angiopathy, in which Abeta42 rather than Abeta40 was predominant. Furthermore, remarkable alpha-synuclein pathology, including LBs and the accumulation of the non-Abeta component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Abeta overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.

Asunto(s)

Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/genética , Amiloide/análisis , Amiloide/genética , Proteínas de la Membrana/análisis , Proteínas de la Membrana/genética , Mutación Missense/genética , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Presenilina-1 , Sinucleínas , alfa-Sinucleína

RESUMEN

Myristoylated alanine-rich C kinase substrate (MARCKS), a protein associated with cell growth, neurosecretion and macrophage activation, is activated by protein kinase C (PKC) phosphorylation. We reported that amyloid beta protein (Abeta) activated MARCKS through a tyrosine kinase and PKC-delta in rat cultured microglia. Here we report that Abeta signaling pathway through a specific PKC isoform is involved in the phosphorylation of MARCKS in Neuro2A cells. Selective PKC inhibitors but not tyrosine kinase inhibitors significantly inhibited the phosphorylation of MARCKS induced by Abeta. Abeta selectively activated PKC-alpha among the four PKC isoforms localized in Neuro2A cells. PKC-alpha activated by Abeta directly phosphorylated a recombinant MARCKS in vitro, Translocation of PKC-alpha from the cytoplasm to the membrane and accumulation of phospho-MARCKS in the cytoplasm were induced by Abeta. These results suggest involvement of a phosphoinositide signaling system through PKC-alpha in the phosphorylation of MARCKS in neurons, an event which may be associated with mechanisms underlying neurotrophic and neurotoxic effects of Abeta.

Asunto(s)

Péptidos beta-Amiloides/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Fosfoproteínas/metabolismo , Proteína Quinasa C/metabolismo , Péptidos beta-Amiloides/farmacología , Animales , Proteínas de Unión al Calcio , Glucosidasas , Humanos , Isoenzimas/metabolismo , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Fosforilación/efectos de los fármacos , Proteína Quinasa C-alfa , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células Tumorales Cultivadas

RESUMEN

Early onset familial Alzheimer disease (FAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. We reported previously a variant form of FAD, due to deletion of exon 9 of PSEN1, with spastic paralysis and rigidity. We describe a novel PSEN1 mutation in a family of Japanese origin with six affected individuals of both genders in two generations. The disease is characterized by presenile dementia, which is preceded by spastic paraparesis and apraxia. This mutation, which is predicted to cause a missense substitution of serine for glycine, occurred at codon 266 in exon 8 of PSEN1. The mutation was not found in 200 controls and 200 sporadic AD patients. On this basis alone, it seems this mutation is pathogenic. Our findings provide a new clue to the etiology of the familial early onset dementia.

Asunto(s)

Demencia/genética , Proteínas de la Membrana/genética , Adulto , Edad de Inicio , Enfermedad de Alzheimer/genética , Secuencia de Aminoácidos , Secuencia de Bases , ADN/química , ADN/genética , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Mutación Missense , Linaje , Presenilina-1 , Homología de Secuencia de Aminoácido

RESUMEN

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.

Asunto(s)

Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Hipocampo/patología , Anciano , Alelos , Apolipoproteína E4 , Atrofia , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad

RESUMEN

Zymomonas mobilis IFO 13 756 could take up galactose and metabolize it so that galactonic acid accumulated in the culture fluid. The oxidation of galactose was catalysed by a membrane-associated enzyme, which could be solubilized with a mixture of 1% Triton X-100 and 1 M: KC1. The strain also accumulated galactitol as a minor metabolite. To confer the ability to utilize galactose on Z. mobilis, a Gal(+) recombinant plasmid, pZG13, was constructed by the insertion of the galETK genes of Escherichia coli immediately downstream of the Z. mobilis promoter gene in pZA22, the plasmid introduced into a Zymomonas strain. Uridine diphospho-glucose 4-epimerase coded in the galE gene was expressed in Z. mobilis carrying pTG13. The recombinant strain could produce a small amount of ethanol from galactose.