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排序方式: 共有155条查询结果,搜索用时 218 毫秒
31.
Guianfranco Mazzei Ryohei Ikegami Nona Abolhassani Naoki Haruyama Kunihiko Sakumi Takashi Saito Takaomi C. Saido Yusaku Nakabeppu 《Aging cell》2021,20(8)
Insulin resistance and diabetes mellitus are major risk factors for Alzheimer''s disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock‐in mouse model, AppNL−F/NL−F , which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6‐month‐old male AppNL−F/NL−F and wild‐type mice were fed a regular or high‐fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild‐type and AppNL−F/NL−F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD‐fed AppNL−F/NL−F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8‐oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in AppNL−F/NL−F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD‐fed AppNL−F/NL−F mice. 相似文献
32.
Keisuke Yagawa Koji Yamano Takaomi Oguro Masahiro Maeda Takehiro Sato Takaki Momose Shin Kawano Toshiya Endo 《Protein science : a publication of the Protein Society》2010,19(4):693-702
Point mutations in proteins can have different effects on protein stability depending on the mechanism of unfolding. In the most interesting case of I27, the Ig‐like module of the muscle protein titin, one point mutation (Y9P) yields opposite effects on protein stability during denaturant‐induced “global unfolding” versus “vectorial unfolding” by mechanical pulling force or cellular unfolding systems. Here, we assessed the reason for the different effects of the Y9P mutation of I27 on the overall molecular stability and N‐terminal unraveling by NMR. We found that the Y9P mutation causes a conformational change that is transmitted through β‐sheet structures to reach the central hydrophobic core in the interior and alters its accessibility to bulk solvent, which leads to destabilization of the hydrophobic core. On the other hand, the Y9P mutation causes a bend in the backbone structure, which leads to the formation of a more stable N‐terminal structure probably through enhanced hydrophobic interactions. 相似文献
33.
Neprilysin (NEP) is a rate-limiting amyloid beta peptide (Abeta)-degrading enzyme in the brain. We demonstrated previously that overexpression of neprilysin in primary cortical neurons remarkably decreased not only extracellular but also intracellular Abeta levels. To investigate the subcellular compartments where neprilysin degrades Abeta most efficiently, we expressed neprilysin chimeric proteins containing various subcellular compartment-targeting domains in neurons. Sec12-NEP, beta-galactoside alpha2,6-sialyltransferase-NEP, transferrin receptor-NEP, and growth-associated protein 43-NEP were successfully sorted to the endoplasmic reticulum, trans-Golgi network, early/recycling endosomes, and lipid rafts, respectively. We found that intracellularly, wild-type neprilysin and all the chimeras showed equivalent Abeta40-degrading activities. Abeta40 was more effectively cleared than Abeta42, and this tendency was greater for intracellular Abeta than for extracellular Abeta. Wild-type and trans-Golgi network-targeted ST-NEP cleared more intracellular Abeta42 than the other chimeras. Wild-type neprilysin cleared extracellular Abeta more effectively than any of the chimeras, among which endoplasmic reticulum-targeted Sec12-NEP was the least effective. These observations indicate that different intracellular compartments may be involved in the metabolism of distinct pools of Abeta (Abeta40 and Abeta42) to be retained or recycled intracellularly and to be secreted extracellularly, and that the endogenous targeting signal in wild-type neprilysin is well optimized for the overall neuronal clearance of Abeta. 相似文献
34.
35.
Naotaka Izuo Nobuhiro Watanabe Yoshihiro Noda Takashi Saito Takaomi C. Saido Koutaro Yokote Harumi Hotta Takahiko Shimizu 《Aging cell》2023,22(11):e13994
Although insulin resistance increases the risk of Alzheimer's disease (AD), the mechanisms remain unclear, partly because no animal model exhibits the insulin-resistant phenotype without persistent hyperglycemia. Here we established an AD model with whole-body insulin resistance without persistent hyperglycemia (APP/IR-dKI mice) by crossbreeding constitutive knock-in mice with P1195L-mutated insulin receptor (IR-KI mice) and those with mutated amyloid precursor protein (AppNL-G-F mice: APP-KI mice). APP/IR-dKI mice exhibited cognitive impairment at an earlier age than APP-KI mice. Since cholinergic dysfunction is a major characteristic of AD, pharmacological interventions on the cholinergic system were performed to investigate the mechanism. Antagonism to a nicotinic acetylcholine receptor α7 (nAChRα7) suppressed cognitive function and cortical blood flow (CBF) response to cholinergic-regulated peripheral stimulation in APP-KI mice but not APP/IR-dKI mice. Cortical expression of Chrna7, encoding nAChRα7, was downregulated in APP/IR-dKI mice compared with APP-KI. Amyloid β burden did not differ between APP-KI and APP/IR-dKI mice. Therefore, insulin resistance, not persistent hyperglycemia, induces the earlier onset of cognitive dysfunction and CBF deregulation mediated by nAChRα7 downregulation. Our mouse model will help clarify the association between type 2 diabetes mellitus and AD. 相似文献
36.
Satoshi Toyoshima Takaomi Saido Fusao Makishima Toshiaki Osawa 《Biochemical and biophysical research communications》1983,114(3):1126-1131
Liposomes having membrane proteins of chicken erythrocytes were prepared and the effect of S-adenosylmethionine on 45Ca2+ uptake into the liposomes was investigated. S-Adenosylmethionine, a donor of methyl groups in enzymatic methylation, induced an increase of 45Ca2+ uptake into the proteoliposomes with membrane proteins but not into the liposomes without membrane proteins. Increased release of 45Ca2+ from the inside of the proteoliposomes was also induced by S-adenosylmethionine. These increases of uptake and release of 45Ca2+ were inhibited by S-adenosylhomocystein, an inhibitor of enzymatic methylation. Furthermore, membrane proteins from chicken erythrocytes showed protein and phospholipid methyltransferase activities. The uptake of other materials, 3-0-[methyl-3H]glucose, α-[1-14C]aminoisobutyric acid, 42K+ and 54Mn2+, into the proteoliposomes was not increased by S-adenosylmethionine. These results suggest that enzymatic methylation of membrane components may have an important role in the regulation of calcium transport in the chicken erythrocyte membrane and this regulation is rather specific for calcium. 相似文献
37.
38.
Dual Roles of Proteasome in the Metabolism of Presenilin 1 总被引:1,自引:0,他引:1
Toshiyuki Honda† Kaori Yasutake‡ Naomi Nihonmatsu Mark Mercken‡ Hiroshi Takahashi Ohoshi Murayama Miyuki Murayama Kazuki Sato‡ Akira Omori‡ Satoshi Tsubuki§ Takaomi C. Saido§ & Akihiko Takashima 《Journal of neurochemistry》1999,72(1):255-261
Abstract : Presenilin 1 (PS1) has been identified as a causative gene for most early-onset familial Alzheimer's disease. Biochemical studies revealed that PS1 exists predominantly as two processed fragments in cells and brain tissues. We prepared stably transfected cells expressing the wild-type and familial Alzheimer's disease-associated mutants of PS1 and investigated the enzyme that participates in the metabolism of PS1. After treatment of the cells with proteasome inhibitors, the full-length PS1 was significantly accumulated. The levels of N- and C-terminal fragments were also increased. The accumulation of PS1 with a deletion of exon 10, which is unable to be processed, on treatment of the transfected cells with lactacystin indicated that proteasome can degrade full-length PS1. A synthetic peptide that includes the processing region of PS1 was cleaved by 20S proteasome at the putative processing sites after Met288 and Glu299 . Metabolic labeling experiments showed that the appearance of the N-terminal fragment was attenuated by the inhibitor. Finally, 28-kDa N- and 20-kDa C-terminal fragments were generated by purified PS1 in vitro. These data indicated that the proteasome pathway is involved in PS1 processing. These results demonstrate that the proteasome pathway plays dual roles in processing and degradation of PS1. 相似文献
39.
The migratory history of Sakhalin taimen, Hucho perryi, was examined in terms of strontium (Sr) and calcium (Ca) uptake in the otolith by using wavelength dispersive X-ray spectrometry on an electron microprobe. Otolioth Sr:Ca ratios of freshwater-reared samples remained consistently at low levels throughout the otolith. The Sr:Ca ratios of samples from Lake Aynskoye of Sakhalin Island showed a low value from the core up to a point of 700–2140µm. Thereafter, the ratios increased sharply and remained at higher levels up to the outermost regions. The difference in Sr:Ca ratio might be the result of the presence of individuals that underwent seawater and freshwater life history phases, probably reflecting the ambient salinity or the seawater–freshwater gradient in Sr concentration. Otolith Sr:Ca ratio analysis revealed downstream migration history in H. perryi. 相似文献
40.
Molecularly imprinted copolymer membranes functionalized by phase inversion imprinting for uracil recognition and permselective binding 总被引:1,自引:0,他引:1
Wang HY Xia SL Sun H Liu YK Cao SK Kobayashi T 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,804(1):127-134
Uracil (URA) was selected as a template for preparing molecularly imprinted membranes of poly(acrylonitrile-co-methylacrylic acid) [P(AN-co-MAA)] using the phase inversion technique. This study used Fourier transform infra-red (FT-IR) and (1)H nuclear magnetic resonance (NMR) spectroscopic studies to characterize the polymer-template interaction and scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphology of the URA imprinted membrane. Resultant membranes had typical ultrafiltration structure with porous morphology and showed a permeation flux of 3.5 x 10 9-5)m(3)/(m(2)s) for 32 microM URA aqueous solution. Permselective binding to the target molecule was observed in permeation experiments with 7.9 micromol/g binding capacity of URA. Binding selectivity was discussed for URA and its analogs, dimethyluracil (DMURA) and caffeine (CAF), with 0.6 and 0.8 micromol/g binding capacity, respectively. 相似文献