Alzheimer Disease: Mishima K

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.

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.

Mishima K. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #15478641 No free full text.

This publication has no abstract.

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.

Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M. · Department of Neuropsychiatry, Akita University School of Medicine, Japan. · Biol Psychiatry. · Pubmed #10071710 No free full text.

Abstract: BACKGROUND: There is growing evidence that the dysregulation of circadian rhythms may play an important role in irregular sleep-waking in demented elderly. In this study, we investigated daily variation of the pineal hormone melatonin, which has been reported to possess hypnogenic and synchronizing effects, in patients with senile dementia of Alzheimer's type. METHODS: Serum melatonin secretion rhythms in inpatients with senile dementia of Alzheimer's type (SDAT group, n = 10, average age = 75.7 years) with disturbed sleep-waking and nondemented elderly (ND group, n = 10, age = 78.3 years) without clinical sleep disorders in the same facility were monitored under a dim light condition without excessive physical exercise. RESULTS: The SDAT group showed a significantly higher degree of irregularities in actigraphically recorded rest-activity (R-A) rhythm during the 7-day baseline period compared with the ND group. The SDAT group simultaneously showed significantly reduced amplitude, larger variation of peak times, and diminished amount of total secretion in the melatonin secretion rhythm compared with the ND group. There were significantly positive correlations between the severity of R-A rhythm disorder and the reduced amplitude as well as diminished amount of total melatonin secretion. CONCLUSIONS: The SDAT patients with disturbed sleep-waking possessed melatonin secretion rhythm disorders that may play an important role in irregular sleep-waking in demented elderly.