Alzheimer Disease: Iwasaki K

Fujiwara H, Tabuchi M, Yamaguchi T, Iwasaki K, Furukawa K, Sekiguchi K, Ikarashi Y, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Yaegashi N, Kase Y, Arai H. · Center for Asian Traditional Medicine, Tohoku University Graduate School of Medicine, Sendai, Aoba-ku, Japan. · J Neurochem. · Pubmed #19457098 No free full text.

Abstract: The deposition of amyloid beta (Abeta) protein is a consistent pathological hallmark of Alzheimer's disease (AD) brains; therefore, inhibition of Abeta fibril formation and destabilization of pre-formed Abeta fibrils is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. This study demonstrated that Paeonia suffruticosa, a traditional medicinal herb, not only inhibited fibril formation of both Abeta(1-40) and Abeta(1-42) but it also destabilized pre-formed Abeta fibrils in a concentration-dependent manner. Memory function was examined using the passive-avoidance task followed by measurement of Abeta burden in the brains of Tg2576 transgenic mice. The herb improved long-term memory impairment in the transgenic mice and inhibited the accumulation of Abeta in the brain. Three-dimensional HPLC analysis revealed that a water extract of the herb contained several different chemical compounds including 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (PGG). No obvious adverse/toxic were found following treatment with PGG. As was observed with Paeonia suffruticosa, PGG alone inhibited Abeta fibril formation and destabilized pre-formed Abeta fibrils in vitro and in vivo. Our results suggest that both Paeonia suffruticosa and its active constituent PGG have strong inhibitory effects on formation of Abeta fibrils in vitro and in vivo. PGG is likely to be a safe and promising lead compound in the development of disease-modifying drugs to prevent and/or cure AD.

Watanabe T, Yamagata N, Takasaki K, Sano K, Hayakawa K, Katsurabayashi S, Egashira N, Mishima K, Iwasaki K, Fujiwara M. · Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan. · Brain Res. · Pubmed #18996097 No free full text.

Abstract: Acetylcholine (ACh) release is one of the key factors in memory mechanisms. To clarify whether beta-amyloid (Abeta) induces a disturbance of the cholinergic system leading to memory impairment, we examined memory impairment and measured hippocampal ACh release in Tg2576 (Tg) mice that over-express the Swedish mutant amyloid precursor protein (APPsw). Furthermore, we examined Abeta burden with aging. Tg mice aged 9-11 months, but not aged 4-6 months, showed memory impairment in the 8-arm radial maze behavior test. Spontaneous ACh release was not altered in Tg mice compared with age-matched control mice at 4-6 or 9-11 months of age. On the other hand, high-K(+)-evoked ACh release was decreased in Tg mice aged 9-11 months, but not in Tg mice aged 4-6 months. Hippocampal Abeta increased in an age-dependent manner, but evident amyloid plaques were not found in the hippocampus of Tg mice aged 11 months. These results suggest that memory impairment in Tg mice could be attributed to cholinergic synapse dysfunction that could not be caused predominantly by amyloid plaques. Measuring ACh release in this model might be a useful index for the screening of new drugs to treat the early-phase of Alzheimer's disease.

Matsui T, Nemoto M, Maruyama M, Yuzuriha T, Yao H, Tanji H, Ootsuki M, Tomita N, Matsushita S, Higuchi S, Yoshida Y, Seki T, Iwasaki K, Furukawa K, Arai H. · Department of Geriatric and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. · Neurodegener Dis. · Pubmed #16909012 No free full text.

Abstract: BACKGROUND: Cerebrovascular disease is common in Alzheimer's disease (AD). Elevated plasma homocysteine (pHcy) levels are reported to be associated with an increased risk of poor cognition and dementia. OBJECTIVE: To determine whether high pHcy levels are associated with an increased risk of coexisting silent brain infarctions (SBIs) in AD. METHODS: Study population comprising 143 outpatients with clinical diagnosis of probable AD (73.3 +/- 7.0 years) were classified into 2 groups according to the presence or absence of SBIs on magnetic resonance imaging. RESULTS: SBIs were noted in 32.9% (47/143) of the AD patients. The pHcy levels in the AD with SBIs (14.0 +/- 4.5 micromol/l) were significant ly elevated compared with the AD without SBIs (11.7 +/- 4.7 micromol/l, p = 0.007). After adjusting for age and gender, high pHcy (>12.4 micromol/l), but not hypertension, was associated with an increased risk of developing SBIs in AD (OR = 4.61, 95% CI = 1.74-12.2, p = 0.002). However, age at onset, cognitive function, cerebrospinal tau or amyloid beta-peptide(1-42) levels were not significantly correlated with pHcy levels in AD. CONCLUSION: SBIs commonly coexist with AD, and may be a unique vascular condition in which homocysteine plays an important role. Homocysteine-lowering therapy rather than antihypertensive medication might be an appropriate strategy to prevent stroke associated with AD.

Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, Tomita N, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Ohizumi Y, Arai H. · Department of Geriatric and Complementary Medicine, Center for Asian Traditional Medicine Research, Tohoku University School of Medicine, Sendai, Japan. · J Neurosci Res. · Pubmed #16676329 No free full text.

Abstract: Because the deposition of beta-amyloid protein (Abeta) is a consistent pathological hallmark of Alzheimer's disease (AD) brains, inhibition of Abeta generation, prevention of Abeta fibril formation, or destabilization of preformed Abeta fibrils would be attractive therapeutic strategies for the treatment of AD. We examined the effects of several medicinal herbs used in traditional Chinese medical formulae on the formation and destabilization of Abeta fibrils by using the thioflavin T binding assay, atomic force microscopic imaging, and electrophoresis. Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively. Significant destabilization of preformed Abeta(1-40) and Abeta(1-42) fibrils was also induced by Uncaria rhynchophylla as well as some other herb extracts. Three-dimensional HPLC analysis indicated that the water extract of this herb contains several different chemical compounds, including oxindole and indol alkaloids, which have been regarded as neuroprotective. Our results suggest that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils, and we conclude that this medicinal herb could have the potency to be a novel therapeutic agent to prevent and/or cure AD.

Egashira N, Iwasaki K, Takashima A, Watanabe T, Kawabe H, Matsuda T, Mishima K, Chidori S, Nishimura R, Fujiwara M. · Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Fukuoka 814-0180, Japan. · Brain Res. · Pubmed #16182262 No free full text.

Abstract: Mutant R406W human tau was originally identified in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and causes a hereditary tauopathy that clinically resembles Alzheimer's disease (AD). In the current study, we examined the performance of R406W transgenic (Tg) mice in the forced swimming test, a test with high predictivity of antidepressant efficacy in human depression, and found an enhancement of the immobility time. In contrast, the motor function and anxiety-related emotional response of R406W Tg mice were normal. Furthermore, a selective serotonin reuptake inhibitor (SSRI), fluvoxamine (100 mg/kg, p.o.), significantly reduced this enhancement of the immobility time, whereas a noradrenaline reuptake inhibitor, desipramine, had no effect. In an in vivo microdialysis study, R406W Tg mice exhibited a significantly decreased extracellular 5-hydroxyindoleacetic acid (5-HIAA) level in the frontal cortex and also exhibited a tendency toward a decreased extracellular 5-hydroxytryptamine (5-HT) level. Moreover, fluvoxamine, which reduced the enhancement of the immobility time, significantly increased the extracellular 5-HT level in R406W Tg mice. These results suggest that R406W Tg mice exhibit changes in depression-related behavior involving serotonergic neurons and provide an animal model for investigating AD with depression.

Horikawa E, Matsui T, Arai H, Seki T, Iwasaki K, Sasaki H. · Division of Physical and Behavioral Support System, Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga. · Intern Med. · Pubmed #16093593 links to  free full text

Abstract: OBJECTIVE: Falls are common in patients with Alzheimer's disease (AD). Identification of the potential risk factors and developing preventive strategies for falls will have a significant impact in maintaining the quality of life in AD. PATIENTS: Clinical follow-up of 124 (74.1+/-6.1 years, range 62-88) mild to moderate AD patients in an outpatient memory clinic. METHODS: Postural sway, cognitive function, use of neuroleptics, severity of periventricular and deep white matter lesions, and the presence or absence of silent brain infarctions on magnetic resonance imaging were assessed at baseline. RESULTS: A total of 104 patients (84%) completed the study. Fall events were confirmed in 42.3% (44/104). After adjustment for age, gender, and cognitive status, a high grade of periventricular white matter lesions (odds ratio 8.7 [95%CI 1.5 to 51.8], p = 0.017) and neuroleptic drug use (odds ratio 3.5 [95%CI 1.2 to 10.5], p = 0.027) were significantly associated with an increased risk of falls. CONCLUSION: Our results suggest that periventricular white matter lesions and the use of neuroleptics may be related to falls in mild to moderate AD. A comprehensive risk management of brain ischemia as well as the use of the smallest efficacious dose of neuroleptics in the treatment of behavioral and psychiatric symptoms of AD should be recommended to help reduce the risk of unexpected falls.

Hatip-Al-Khatib I, Takashi A, Egashira N, Iwasaki K, Fujiwara M. · Division of Internal Medicine, Department of Pharmacology, Faculty of Medicine, Pamukkale University, Denizli 20070, Turkey. · Brain Res. · Pubmed #15158174 No free full text.

Abstract: The effects of zanapezil (TAK-147) and donepezil (E2020) on extracellular acetylcholine (ACh) levels were investigated by HPLC-microdialysis of ventral hippocampus (VH) in freely moving intact rats. The results showed that the basal ACh release rate in the VH is 116.7 +/- 12.4 to 158.4 +/- 22.86 fmol/20 microl. At 2, 5 and 10 mg/kg, single p.o., each drug increased ACh level by 9.4%, 106.5%, 50.8% (TAK-147) and 14.8%, 76.1%, 120.94% (E2020), respectively. The ED50 values were 4.52 mg/kg (1.43 - 14.29; R=0.52) and 4.07 mg/kg (1.77 - 9.37; R=0.985) for TAK-147 and E2020, respectively. Analysis of data revealed that the relative TAK-147/E2020 potency ratio is 0.773, but the effect of E2020 was accompanied by more prominent skeletal muscle fasciculation, gnawing, increased defecation and to lesser extent salivation. Moreover, the significant effect of TAK-147 was observed earlier (20 min) than E2020 (60 min). In this study, we also investigated the effect of both drugs at dose of 5 mg/kg p.o. on blood flow in the VH using Laser Doppler Flowmetry. The results showed that the average blood flow rate in the VH is 6.5 +/- 0.9 ml/min/100 g. TAK-147 did not change blood flow, but E2020 increased blood flow in a biphasic manner. The first increment was obtained between 5 and 40 min (11.5 +/- 2.2 to 12.7 +/- 2.2 ml/min/100 g), and the second one 80-105 min (10.7 +/- 1.6 to 13.4 +/- 3.6 ml/min/100 g). In conclusion, the present results indicate that both TAK-147 and E2020 increase ACh level in the VH. E2020 showed greater potency than TAK-147, but it induced more fasciculation and other side effects than TAK-147. Moreover, the blood flow increasing properties of E2020 could be beneficial in some patients with Alzheimer' disease especially those with chronic vascular dementia, but at the same time, it could also indicate less specific ACh increasing activity than TAK-147 and higher risk of cerebral hemorrhage. On the other hand, the fast and specific effect of TAK-147 may be useful for cure of early stages of Alzheimer's disease (AD).

Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A. · Laboratory for Alzheimer's Disease and Neural Architecture, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. · Proc Natl Acad Sci U S A. · Pubmed #12368474 links to  free full text

Abstract: The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease. Expression of modest levels of the longest human tau isoform with this mutation under the control of the alpha-calcium-calmodulin-dependent kinase-II promoter in transgenic (Tg) mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wild-type tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Straight tau filaments were recovered from Sarkosyl-insoluble fractions from only the aged Tg brains. Behaviorally, aged Tg mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice that exhibit a phenotype mimicking R406W FTDP-17 provide an animal model for investigating the adverse properties associated with this mutation, which might potentially recapitulate some etiological events in Alzheimer's disease.

Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B. · Department of Pharmacology and Neuroscience Program, Loyola University Medical Center, Maywood, Illinois 60153, USA. · J Biol Chem. · Pubmed #11504726 links to  free full text

Abstract: Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits functional roles regulating growth and development. For instance, PS1 binds to beta-catenin and modulates beta-catenin signaling. In the current study, we observed that knockout of PS1 inhibited beta-catenin-mediated transcription by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. Overexpressing wild-type PS1 increased beta-catenin-mediated transcription by 37.5%, and overexpressing PS1 with mutations associated with Alzheimer's disease decreased beta-catenin-mediated transcription by 66%. To examine whether regulation of beta-catenin by PS1 requires phosphorylation by glycogen synthase kinase 3beta (GSK 3beta), we examined whether inhibiting GSK 3beta activity overcomes the inhibition of beta-catenin transcription induced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 were treated with LiCl, which inhibits GSK 3beta, or transfected with beta-catenin constructs that lack the GSK 3beta phosphorylation sites. Neither treatment overcame PS1-mediated inhibition of beta-catenin signaling, suggesting that regulation of beta-catenin by PS1 was not affected by the activity of GSK 3beta. To investigate how PS1 might regulate beta-catenin signaling, we determined whether PS1 interacts with other elements of the beta-catenin signaling cascade, such as the Tcf-4 transcription factor. Coimmunoprecipitation studies showed binding of PS1 and hTcf-4, and examining nuclear isolates indicated that nuclear hTcf-4 was decreased in cells expressing mutant PS1. These data show that PS1 interacts with multiple components of the beta-catenin signaling cascade and suggest that PS1 regulates beta-catenin in a manner independent of GSK 3beta activity.

Wang Q, Iwasaki K, Suzuki T, Arai H, Ikarashi Y, Yabe T, Toriizuka K, Hanawa T, Yamada H, Sasaki H. · Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan. · Phytomedicine. · Pubmed #10969717 No free full text.

Abstract: The effects of a traditional Japanese herbal medicine, Kami-Untan-To (KUT), on brain choline (Ch) and Acetylcholine (ACh) levels in aged mice were examined. Further, the expression of choline acetyltransferase (ChAT) in the medial septum (MS), the vertical limbs of the diagonal band of Broca (VDB), and the nucleus basalis Meynert (NBM) was examined by immunohistochemistry. Following an oral administration of KUT to the aged mice for 3 months, ACh levels in the cortex, striatum and hippocampus were increased significantly. The density of ChAT-immunoreactive cells located in MS, VDB, and NBM in the KUT-treated group was increased significantly as compared to the non-treatment group. The survival rate of aged mice was significantly higher in the KUT-treated group as compared to that in the nontreated group. Our results suggest that KUT potentiates the brain acetylcholinergic system, and may become a possible anti-dementia drug.

Maruyama M, Tomita N, Iwasaki K, Ootsuki M, Matsui T, Nemoto M, Okamura N, Higuchi M, Tsutsui M, Suzuki T, Seki T, Kaneta T, Furukawa K, Arai H. · No affiliation provided · J Am Geriatr Soc. · Pubmed #16696770 No free full text.

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