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Biomedical subjects

Masatoshi Takeda

Publications and source records attributed to Masatoshi Takeda.

At least 73 records · Page 4Linked to original sources
PubMed2003

[Biological markers for Alzheimer disease].

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.

Alzheimer Disease↗
PubMed2003

[Nightmares].

Explore the source record for details and available documents.

Adult↗
PubMed2002

Role of protein kinase B in Alzheimer's neurofibrillary pathology.

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

Adult↗
PubMed2002

Parallel distributed processing neuroimaging in the Stroop task using spatially filtered magnetoencephalography analysis.

Parallel distributed processing neuroimaging in the Stroop color word interference task in five healthy subjects was studied. The total reaction time was set at 650 ms with a time window of 200 ms in steps of 50 ms. Spatially filtered magnetoencephalography analysis, as used in synthetic aperture magnetometry, was used. Neural activation began in the left posterior parietal-occipital area (150-250 ms post-stimulus), followed by the right prefrontal polar area (250-350 ms), the left dorsolateral prefrontal cortex (250-400 ms), and the mid- to lower- primary motor area (350-400 ms). Successive and temporally overlapping activation of various cortical regions were successfully estimated within a short 200 ms time interval, contrary to previous positron emission tomography and fMRI studies.

Adult↗
PubMed2002

Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation.

The beta-amyloid precursor protein (beta APP) is proteolytically processed by two secretase activities to produce the pathogenic amyloid beta-peptide (A beta). N-terminal cleavage is mediated by beta-secretase (BACE) whereas C-terminal intramembraneous cleavage is exerted by the presenilin (PS) gamma-secretase complex. The A beta-generating gamma-secretase cleavage principally occurs after amino acid 40 or 42 and results in secretion of A beta-(1-40) or A beta-(1-42). Upon overexpression of BACE in cultured cells we unexpectedly noticed a reduction of secreted A beta-(1-40/42). However, mass spectrometry revealed a truncated A beta species, which terminates at amino acid 34 (A beta-(1-34)) suggesting an alternative gamma-secretase cut. Indeed, expression of a loss-of-function variant of PS1 inhibited not only the production of A beta-(1-40) and A beta-(1-42) but also that of A beta-(1-34). However, expression levels of BACE correlate with the amount of A beta-(1-34), and A beta-(1-34) is produced at the expense of A beta-(1-40) and A beta-(1-42). Since this suggested that BACE is involved in a C-terminal truncation of A beta, we incubated purified BACE with A beta-(1-40) in vitro. Under these conditions A beta-(1-34) was generated. Moreover, when conditioned media containing Abeta-(1-40) and A beta-(1-42) were incubated with cells expressing a loss-of-function PS1 variant together with BACE, A beta-(1-34) was efficiently produced in vivo. These data demonstrate that an apparently gamma-secretase-dependent A beta derivative is produced after the generation of the non-truncated A beta via an additional and unexpected activity of BACE.

Alzheimer Disease↗
PubMed2002

MEG study of long-term cortical reorganization of sensorimotor areas with respect to using chopsticks.

The movements required to use chopsticks are overlearned and routine in Asians. Most non-Asians, on the other hand, typically have difficulty performing this unfamiliar manual activity, and have to focus their attention on the movements required to use chopsticks adequately. Using magnetoencephalography (MEG) we compared the cortical activation of highly trained Asian chopstick users to the activation of Europeans who only occasionally used chopsticks, while they performed the same tasks with chopsticks or a control task of simple tapping of the same fingers. The data were analyzed using the new method of synthetic aperture magnetometry (SAM). In Europeans there was a significantly higher ratio of spectral power in the higher gamma frequency band (60-80 Hz) over the sensorimotor area compared to the Asian subjects. From these results we conclude that the high gamma band activity in the sensorimotor area may reflect focused attention and functional reorganization of the cortical network with respect to sensorimotor experience.

Adult↗
PubMed2002

Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1.

Following ectodomain shedding, Notch-1 undergoes presenilin (PS)-dependent constitutive intramembranous endoproteolysis at site-3. This cleavage is similar to the PS-dependent gamma-secretase cleavage of the beta-amyloid precursor protein (betaAPP). However, topological differences in cleavage resulting in amyloid beta-peptide (Abeta) or the Notch-1 intracellular domain (NICD) indicated independent mechanisms of proteolytic cleavage. We now demonstrate the secretion of an N-terminal Notch-1 Abeta-like fragment (Nbeta). Analysis of Nbeta by MALDI-TOF MS revealed that Nbeta is cleaved at a novel site (site-4, S4) near the middle of the transmembrane domain. Like the corresponding cleavage of betaAPP at position 40 and 42 of the Abeta domain, S4 cleavage is PS dependent. The precision of this cleavage is affected by familial Alzheimer's disease-associated PS1 mutations similar to the pathological endoproteolysis of betaAPP. Considering these similarities between intramembranous processing of Notch and betaAPP, we conclude that these proteins are cleaved by a common mechanism utilizing the same protease, i.e. PS/gamma-secretase.

Alzheimer Disease↗
PubMed2002

Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide.

Alzheimer's disease (AD)-associated gamma-secretase is a presenilin (PS)- dependent proteolytic activity involved in the intramembraneous cleavage of the beta-amyloid precursor protein, Notch, LDL receptor-related protein, E-cadherin, and ErbB-4. This cut produces the corresponding intracellular domains (ICD), which are required for nuclear signaling of Notch and probably ErbB-4, the beta-amyloid precursor protein, E-cadherin, and the LDL receptor-related protein as well. We have now investigated CD44, a cell surface adhesion molecule, which also undergoes an intramembraneous cleavage to liberate its ICD. We demonstrate that this cleavage requires a PS-dependent gamma-secretase activity. A loss-of-function PS1 mutation, a PS1/PS2 knockout, as well as two independent and highly specific gamma-secretase inhibitors, abolish this cleavage. Surprisingly, small peptides similar to the amyloid beta-peptide (Abeta) are generated by an additional cut in the middle of the transmembrane region of CD44. Like Abeta, these CD44 beta-peptides are generated in a PS-dependent manner. These findings therefore suggest a dual intramembraneous cleavage mechanism mediated by PS proteins. The dual cleavage mechanism is required for nuclear signaling as well as removal of remaining transmembrane domains, a general function of PS in membrane protein metabolism.

Alzheimer Disease↗
PubMed2002

FAD-linked presenilin-1 mutants impede translation regulation under ER stress.

FAD mutations in presenilin-1 (PS1) cause attenuation of the induction of the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP under ER stress, due to disturbed function of IRE1, the sensor for accumulation of unfolded protein in the ER lumen. PERK, an ER-resident transmembrane protein kinase, is also a sensor for the unfolded protein response (UPR), causing phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) to inhibit translation initiation. Here, we report that the FAD mutant PS1 disturbs the UPR by attenuating both the activation of PERK and the phosphorylation of eIF2alpha. Consistent with the results of a disturbed UPR, inhibition of protein synthesis under ER stress was impaired in cells expressing PS1 mutants. These results suggest that mutant PS1 impedes general translational attenuation regulated by PERK and eIF2alpha, resulting in an increased load of newly synthesized proteins into the ER and subsequently increasing vulnerability to ER stress.

Alzheimer Disease↗