Alzheimer Disease: Takeda M

Tagami S, Okochi M, Fukumori A, Takeda M. · Laboratory Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan. · Nihon Shinkei Seishin Yakurigaku Zasshi. · Pubmed #19108503 No free full text.

Abstract: Presenilin (PS)/gamma-secretase degrades transmembrane domains of betaAPP and Notch-1, generating Abeta and NICD. Some cleavages by PS/gamma-secretase have diversity. gamma-Cleavage of betaAPP occurs mainly at residue 40 (gamma40) and at residue 42 (gamma42), producing Abeta 40 and Abeta42, respectively. An increase in the proportion of gamma42 to gamma40 cleavage is consistently observed in many familial Alzheimer disease-associated PS or betaAPP mutants, but it is unclear whether such changes in the precision of PS/gamma-secretase have any biological effects. We found that S3 cleavage of Notch-1 by PS/gamma-secretase has diversity, resulting in the production of two types of NICD with distinct ability to transmit Notch signaling. We also showed that the precision of S3 cleavage and Notch signaling intensity can be modulated by physiological factors. Although some PS/gamma-secretase modulators (GSM) have been known to change the precision of gamma-cleavage, it is unknown whether there are any modulators which change the S3 cleavage precision. We found such a compound increasing Notch signaling intensity. Our findings suggest that i) abnormally up-or-down regulated Notch signaling may be corrected by modifying the S3 cleavage precision and that ii) effects on the S3 cleavage precision should be carefully examined in developments of GSM lowering Abeta42 for AD therapeutics.

Tagami S, Okochi M, Fukumori A, Jiang J, Yanagida K, Nakayama T, Morihara T, Tanaka T, Kudo T, Takeda M. · Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka, Japan. · Neurodegener Dis. · Pubmed #18322378 No free full text.

Abstract: BACKGROUND/AIMS: Following extracellular shedding, transmembrane domains (TMs) of beta-amyloid precursor protein (betaAPP) and Notch-1 undergo proteolysis by presenilin (PS)/gamma-secretase at least at two sites, near the middle of the TM (gamma-/S4 cleavage) and at the interface between cytosol and the TM (epsilon-/S3 cleavage), releasing Alzheimer disease (AD)-associated beta-amyloid (Abeta)/Notch-1beta (Nbeta) and betaAPP intracellular cytoplasmic domain (AICD)/Notch-1 intracellular cytoplasmic domain (NICD). Inhibiting PS/gamma-secretase activity is an essential approach to AD treatment, but it also decreases NICD production, which may cause severe side effects. Therefore, it is important to investigate the differences between the cleavages at the two sites. Gamma-/S4 and epsilon-cleavages have diversity, and produce a number of Abeta/Nbeta and AICD species. S3 cleavage diversity has been recently identified. It is significant that each cleavage occurs with strict precision, not randomly. METHODS: Biochemical analysis of cultured cells was performed to explore the processing mechanisms. RESULTS: Familial AD-associated PS1 mutations as well as a subset of nonsteroidal anti-inflammatory drugs cause similar changes in gamma-/S4 cleavage precision, suggesting a common process for these cleavages near the middle of the TM. While the precision of the epsilon-cleavage is drastically affected by physiological factors, that of epsilon-/S3 cleavage is not. CONCLUSION: The processes of the two cleavages occurring in different portions of TMs may be diverse, thus representing possible targets for anti-AD therapeutics to selectively reduce Abeta.

Mori K, Takeda M. · Osaka University Graduate School of Medicine, Department of Psychiatry, Japan. · Clin Calcium. · Pubmed #17767023 No free full text.

Abstract: Estrogen has its receptor in the brain and affects the nervous system in various ways. To date, it has been paid attention whether the cognitive function and the risk of depression change due to estrogen deficiency and also whether these changes respond to hormone replacement therapy (HRT). The increase in female life expectancy accelerates the prevalence of dementia like Alzheimer Disease, so the efficacy of HRT in the cognitive function got the public attention. On the contrary, a series of large-scale randomized controlled trials (Women's Health Initiative Memory Study: WHIMS) in aged 65 years or older women showed HRT increases the risk of dementia. However, certain studies indicate HRT may have beneficial effect on dementia when being started earlier. Therefore direct application of the result of WHIMS for the climacteric women is still controversial.

Sunderland T, Hampel H, Takeda M, Putnam KT, Cohen RM. · Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16880359 No free full text.

Abstract: Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.

Takeda M, Tanaka T, Kudo T, Okochi M, Kamino A, Tagami S. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #15770965 No free full text.

This publication has no abstract.

Takeda M. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #15152656 No free full text.

This publication has no abstract.

Okochi M, Takeda M. · Department of Psychiatry, Osaka University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #15011326 No free full text.

This publication has no abstract.

Tanii H, Takeda M. · Department of Clinical Neuroscience, Psychiatry, Osaka University Graduate School of Medicine. · Ryoikibetsu Shokogun Shirizu. · Pubmed #14626111 No free full text.

This publication has no abstract.

Tanaka T, Wada K, Yamamori H, Tanaka S, Kudo T, Takeda M. · Department of Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine. · Seishin Shinkeigaku Zasshi. · Pubmed #12806899 No free full text.

Abstract: The development of diagnostic markers for earlier and more reliable diagnosis of Alzheimer disease (AD) is essential, particularly because therapeutic medication is available for AD. Cerebrospinal fluid (CSF) is a useful source of diagnostic information. Previously we found the increase of total tau protein in CSF in normal pressure hydrocephalus patients, and others reported the increase also in corticobasal degeneration and frontotemporal dementia. To differentiate the AD from other diseases, further approach was employed and oxidized protein in CSF was investigated. Heat stable fractions of CSF were analyzed on the content of carbonyl residues, which are derivatives of protein oxidization. The result suggests that protein oxidation is highly involved in AD and that this method might be useful to differentiate AD from other neurological disease.

Okochi M, Takeda M. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #12701215 No free full text.

This publication has no abstract.

Cacabelos R, Fernández-Novoa L, Lombardi V, Takeda M. · EuroEspes Biomedical Research Center, Institute for CNS Disorders, Spain. · Seishin Shinkeigaku Zasshi. · Pubmed #12701212 No free full text.

This publication has no abstract.

Tanaka T, Takeda M. · Department of Psychiatry and Behavioral Science, Osaka University, Graduate School of Medicine, D 3, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan. · No To Shinkei. · Pubmed #12428364 No free full text.

This publication has no abstract.

Kamino K, Tanaka T, Kida T, Ohkochi M, Tanii H, Kudo T, Takeda M. · Division of Psychiatry and Behavioral Proteomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, 2-2, D3, Yamadaoka, Suita, 565-0871 Japan. · Nihon Shinkei Seishin Yakurigaku Zasshi. · Pubmed #12373863 No free full text.

Abstract: Lipid metabolism in the central nervous system has been focused as an important factor of Alzheimer's disease, since the apolipoprotein E gene was discovered as a genetic risk for the disease. Lipid metabolism in the brain, showing relatively closed environment, necessitates lipid reutilization. Cerebrospinal fluid contains only high-density lipoproteins composed of apoE and apoJ secreted from astrocytes and of apoA-I and apoA-II transported via the blood brain barrier. These apolipoproteins can bind to beta amyloid and possibly relate to its clearance. The aggregation of phosphorylated tau, found in neurofibrillary tangles in Alzheimer's brain, is also found in the brain with Niemann-Pick disease, suggesting that the impairment of lipid transport in neuronal cells participates in Alzheimer's disease. Mitochondrial function, lipid production, and acetylcholine production are closely related, and these alterations could be involved in cholinergic dysfunction in Alzheimer's disease. The regulation of lipid metabolism in and outside the brain could be a therapeutic and preventive target for Alzheimer's disease.

Kudo T, Takeda M. · Osaka University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #11808269 No free full text.

This publication has no abstract.

Winblad B, Brodaty H, Gauthier S, Morris JC, Orgogozo JM, Rockwood K, Schneider L, Takeda M, Tariot P, Wilkinson D. · Karolinska Institutet, Alzheimer Research Center, Huddinge University Hospital, Stockholm, Sweden. · Int J Geriatr Psychiatry. · Pubmed #11466744 No free full text.

Abstract: The traditional aim of Alzheimer's disease treatment in clinical trials has been to improve cognitive abilities. It has become increasingly clear, however, that other aspects are important in assessing treatment responses. A group of 10 physicians recently gathered to review the current criteria for assessing treatment success in Alzheimer's disease. While cognition has been previously viewed as the primary measure of efficacy, areas such as functional abilities, behaviour, caregiver burden, quality of life and resource utilization all need to be comprehensively assessed to fully evaluate treatment effects in patients with Alzheimer's disease, as well as their impacts on caregivers and society. Postponing or slowing decline in any of these areas may represent an important benefit and should be considered as an outcome measure in clinical trials, clinical practice and decision-making about healthcare budgets. Accepted instruments are available for assessing outcomes in each aspect of Alzheimer's disease, but they need to be selected carefully to provide valid, meaningful data. Some of the most frequently used outcome measures in Alzheimer's disease are reviewed. Using expanded criteria for treatment success and clinically relevant outcome measures, data from currently available studies show that cholinesterase inhibitors produce clinically meaningful long-term benefits in multiple domains in patients with Alzheimer's disease.

Shinosaki K, Nishikawa T, Takeda M. · Department of Clinical Neuroscience, Osaka University, Graduate School of Medicine, Japan. · Psychiatry Clin Neurosci. · Pubmed #11145458 No free full text.

Abstract: Recent dementia studies indicate that behavioral and psychological symptoms of dementia (BPSD) are not merely an epiphenomenon of cognitive impairment, but could be attributed to specific biological brain dysfunction. We describe findings from different research modalities related with BPSD (psychopathological, neuropsychological, neurochemical, and psychophysiological strategies), and attempt to reconcile them into the more integrated form. Characteristics of delusions in dementia patients should be studied in more detail from a psychopathological aspect, aiming for the integration of psychopathology and neurobiology. Imperfect integration of memory function and cognitive function, assigned to the limbic systems and association areas, respectively, may result in BPSD. More intimate collaboration of psychopathological and neurobiological study would be fruitful to promote the research in psychological basis of BPSD. Neurochemical studies indicated that density of extracellular tangles and/or PHF-tau protein have relationships with delusion or misidentification. These changes in neurochemical parameters should be the key to understanding the pathogenesis of BPSD. More importantly, neurochemical and psychological study could be linked by the research in psychophysiology. Computer-assisted electroencephalogram analysis suggests that the right posterior hemisphere shows significant age-associated change earlier than the left in the elderly. Cerebral metabolic rate by positron emission tomography study indicates that paralimbic, left medial temporal, and left medial occipital area are involved in pathogenesis of BPSD in some dementia patients.

Takeda M, Shinosaki K, Nishikawa T, Tanaka T, Kudo T, Nakamura Y, Kashiwagi Y. · Department of Clinical Neuroscience, Osaka University Graduate School of Medicine, Japan. · Nippon Yakurigaku Zasshi. · Pubmed #10876794 No free full text.

Abstract: Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.

Kudo T, Imaizumi K, Tanimukai H, Katayama T, Sato N, Nakamura Y, Tanaka T, Kashiwagi Y, Jinno Y, Tohyama M, Takeda M. · Department of Clinical Neuroscience, Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan. · Neurobiol Aging. · Pubmed #10867206 No free full text.

Abstract: Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.

Cacabelos R, Takeda M, Winblad B. · Institute for CNS Disorders, EuroEspes Biomedical Research Center, La Coruña, Spain. · Int J Geriatr Psychiatry. · Pubmed #10029935 No free full text.

This publication has no abstract.

Miyoshi N, Kazui H, Ogino A, Ishikawa M, Miyake H, Tokunaga H, Ikejiri Y, Takeda M. · Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine, Osaka, Japan. · Dement Geriatr Cogn Disord. · Pubmed #15908748 No free full text.

Abstract: We compared the scores of the Frontal Assessment Battery (FAB), initial fluency subtest, category fluency subtest and subtests of the Mini-Mental State Examination (MMSE) between patients with idiopathic normal pressure hydrocephalus (iNPH) and age-, sex- and MMSE-matched patients with Alzheimer's disease (AD). In patients with iNPH, the time and number of steps required to go and come back a 10-meter distance were measured (Walking test) and the associations between the scores of the cognitive tests and the performance of the Walking test were evaluated. The scores of the FAB and initial fluency subtest in patients with iNPH were significantly lower than those in patients with AD. The scores of the FAB, initial fluency subtest and serial 7 subtest of the MMSE significantly correlated with the two scores of the Walking test in patients with iNPH. The present results indicate that frontal lobe functions were impaired in patients with iNPH and that cognitive impairment was closely associated with gait disturbance in patients with iNPH.

Homma A, Takeda M, Imai Y, Udaka F, Hasegawa K, Kameyama M, Nishimura T. · Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. · Dement Geriatr Cogn Disord. · Pubmed #11044775 No free full text.

Abstract: This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer's disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer's disease.

Kimura R, Yamamoto M, Morihara T, Akatsu H, Kudo T, Kamino K, Takeda M. · Department of Psychiatry, Osaka General Medical Center, Osaka, Japan. · Neurosci Lett. · Pubmed #19539718 No free full text.

Abstract: A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-epsilon 4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.

Kamagata E, Kudo T, Kimura R, Tanimukai H, Morihara T, Sadik MG, Kamino K, Takeda M. · Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan. · Biochem Biophys Res Commun. · Pubmed #19126407 No free full text.

Abstract: Late-onset Alzheimer's disease (LOAD) is significantly associated with a single nucleotide polymorphism located in the dynamin (DNM) 2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. In this study we used real-time PCR to show that DNM2 mRNA is significantly reduced in the cortex of AD brains and in the peripheral blood of dementia patients. Neuroblastoma cells transfected with a dominant negative DNM2 had increased amyloid beta protein (Abeta) secretion and most of the amyloid precursor protein (APP) in these cells was localized to the plasma membrane. In addition, these cells were rich in flotillin, which is a component of lipid rafts. These data suggest that DNM2 expression is reduced in LOAD, which results in the accumulation of APP in lipid raft-rich plasma membranes. Consequently, Abeta secretion may increase in LOAD neurons.

Sadik G, Tanaka T, Kato K, Yamamori H, Nessa BN, Morihara T, Takeda M. · Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan. · J Neurochem. · Pubmed #19014373 No free full text.

Abstract: The microtubule associated protein tau is a major component of neurofibrillary tangles in Alzheimer disease brain, however the neuropathological processes behind the formation of neurofibrillary tangles are still unclear. Previously, 14-3-3 proteins were reported to bind with tau. 14-3-3 Proteins usually bind their targets through specific serine/threonine -phosphorylated motifs. Therefore, the interaction of tau with 14-3-3 mediated by phosphorylation was investigated. In this study, we show that the phosphorylation of tau by either protein kinase A (PKA) or protein kinase B (PKB) enhances the binding of tau with 14-3-3 in vitro. The affinity between tau and 14-3-3 is increased 12- to 14-fold by phosphorylation as determined by real time surface plasmon resonance studies. Mutational analyses revealed that Ser214 is critical for the phosphorylation-mediated interaction of tau with 14-3-3. Finally, in vitro aggregation assays demonstrated that phosphorylation by PKA/PKB inhibits the formation of aggregates/filaments of tau induced by 14-3-3. As the phosphorylation at Ser214 is up-regulated in fetal brain, tau's interaction with 14-3-3 may have a significant role in the organization of the microtubule cytoskeleton in development. Also as the phosphorylation at Ser214 is up-regulated in Alzheimer's disease brain, tau's interaction with 14-3-3 might be involved in the pathology of this disease.

Kurimoto R, Ishii R, Canuet L, Ikezawa K, Azechi M, Iwase M, Yoshida T, Kazui H, Yoshimine T, Takeda M. · Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan. · Neurosci Lett. · Pubmed #18634854 No free full text.

Abstract: In patients with Alzheimer's disease (AD), it is sometimes challenging to identify typical findings in electroencephalography (EEG) or magnetoencephalography (MEG) such as a slowing of the posterior dominant activity or an increase in slow activity. In this MEG study, we evaluated the event-related synchronization (ERS) of alpha activity after eye closing in patients with early AD and mild cognitive impairment (MCI) who presented no slow MEG pattern. Thirteen patients with probable AD and thirteen patients with MCI, who met NINCDS-ADRDA and Petersen's diagnostic criteria, respectively, were enrolled. We also selected fourteen age-matched normal control subjects. MEG activity was acquired during eye-open and eye-closed states. The ERS after eye closing within 8-15Hz frequency band was calculated and its cortical source was superimposed on the individual's MRI by using the beamformer implemented in Brain Electrical Source Analysis (BESA). The Source image was converted into a standardized image, and group comparisons across patients with AD, MCI and controls were performed using BrainVoyager QX. The averaged ERS was observed dominantly in posterior regions in all three groups. Significant difference in ERS was observed only for the comparison between AD patients and controls, with AD patients showing increased ERS in frontal regions. Frontal shift of posterior alpha activity was observed clearly in AD patients using the combination of beamformer and group comparison.