69 research outputs found
Reconsider Alzheimer's disease by the 'calpainâcathepsin hypothesis'âA perspective review
Alzheimer's disease (AD) is characterized by slowly progressive neuronal death, but its molecular
cascade remains elusive for over 100 years. Since accumulation of autophagic vacuoles (also called
granulo-vacuolar degenerations) represents one of the pathologic hallmarks of degenerating neurons in
AD, a causative connection between autophagy failure and neuronal death should be present. The aim of
this perspective review is at considering such underlying mechanism of AD that age-dependent
oxidative stresses may affect the autophagic-lysosomal system via carbonylation and cleavage of heat-
shock protein 70.1 (Hsp70.1). AD brains exhibit gradual but continual ischemic insults that cause
perturbed Ca2+ homeostasis, calpain activation, amyloid b deposition, and oxidative stresses. Membrane
lipids such as linoleic and arachidonic acids are vulnerable to the cumulative oxidative stresses,
generating a toxic peroxidation product 'hydroxynonenal' that can carbonylate Hsp70.1. Recent data
advocate for dual roles of Hsp70.1 as a molecular chaperone for damaged proteins and a guardian of
lysosomal integrity. Accordingly, impairments of lysosomal autophagy and stabilization may be driven
by the calpain-mediated cleavage of carbonylated Hsp70.1, and this causes lysosomal permeabilization
and/or rupture with the resultant release of the cell degradation enzyme, cathepsins (calpainâcathepsin
hypothesis). Here, the author discusses three topics; (1) how age-related decrease in lysosomal and
autophagic activities has a causal connection to programmed neuronal necrosis in sporadic AD, (2) how
genetic factors such as apolipoprotein E and presenilin 1 can facilitate lysosomal destabilization in the
sequential molecular events, and (3) whether a single cascade can simultaneously account for
implications of all players previously reported. In conclusion, Alzheimer neuronal death conceivably
occurs by the similar 'calpain-hydroxynonenal-Hsp70.1-cathepsin cascade' with ischemic neuronal
death. Blockade of calpain and/or extra-lysosomal cathepsins as well as scavenging of hydroxynonenal
would become effective AD therapeutic approaches
A putative link of PUFA, GPR40 and adult-born hippocampal neurons for memory
é沢倧åŠå»è¬ä¿å¥ç 究åãå»åŠç³»Long chain polyunsaturated fatty acids (PUFA) such as docosahexaenoic and arachidonic acids, which are enriched in the brain, are important for multiple aspects of neuronal development and function including neurite outgrowth, signal transduction and membrane fluidity. Recent studies show that PUFA are capable of improving hippocampal long-term potentiation, learning ability of aged rats, and cognitive function of humans with memory deficits, although the underlying mechanisms are unknown. There have been several reports studying physiological roles of G-protein coupled receptor 40 (GPR40) in the pancreas, but no studies have focused on the function of GPR40 in the brain. As GPR40 was recently identified in neurons throughout the brain, it is probable that certain PUFA may act, as endogenous ligands, on GPR40 at their cell surface. However, the effects of PUFA upon neuronal functions are still not clearly understood. Here, although circumferential, a combination of in vitro and in vivo data is introduced to consider the effects of docosahexaenoic and arachidonic acids on brain functions. GPR40 was found in the newborn neurons of the normal and postischemic hippocampi of adult macaque monkeys, while the positive effects of PUFA upon Ca2+ mobilization and cognitive functions were demonstrated in both GPR40 gene-transfected PC12 cells and human subjects with memory deficits. The purpose of this review is to propose a putative link among PUFA, GPR40, and hippocampal newborn neurons by discussing whether PUFA can improve memory functions through GPR40 activation of adult-born neurons. At present, little is known about PUFA requirements that make possible neurogenesis in the adult hippocampus. However, the idea that \u27PUFA-GPR40 interaction might be crucial for adult neurogenesis and/or memory\u27 should be examined in detail using various experimental paradigms. © 2007 Elsevier Ltd. All rights reserved
ã«ã«ãã€ã³ãšã«ããã·ã³ã®åæ ããèŠãéé·é¡ã®èè¡æ§ç¥çµçŽ°èæ»ã®ç æ ãšæ²»ç
é沢倧åŠå»åŠéšæµ·éŠ¬ã®CA-1ãã¥ãŒãã³ã¯è¿æèšæ¶ãæ
ã£ãŠããããäžéæ§ã®è³èè¡ã«è匱ã§çæéè¡æµãé絶ããã ãã§ãããã®æ°æ¥åŸã«ã¯å£æ»ã«é¥ãåäœã¯èšæ¶é害ããããããã®é
çºæ§ç¥çµçŽ°èæ»ã«é¢ããŠã¯çŸåšãªããã®ç
æ
ã¯ããŒã«ã«ãããããŠããæå¹ãªæ²»çæ³ããªããæã
ã¯ãµã«ã®è³èè¡å®éšã§æŽ»æ§åmuã«ã«ãã€ã³ã®åºè³ªã¯ãªãœãœãŒã èã«ååšããããšãåã³muã«ã«ãã€ã³ã®æŽ»æ§åãå æ°Žå解é
µçŽ ã§ããã«ããã·ã³Bã®ãªãœãœãŒã å€ãžã®æŸåºãæ¹èµ·ããããšã瀺åããç¥èŠãåŸããå³ã¡ã掻æ§åmuã«ã«ãã€ã³ã®ã¿ãèªèããæäœãçšããå
ç«æè²ãè¡ããšãèè¡ããããŠããªã海銬ã®CA-1ãã¥ãŒãã³ã¯å
šãæè²ãããªãã®ã«å¯Ÿãã20åéã®è³èè¡ãè² è·åŸã®CA-1ãã¥ãŒãã³ã¯ãæ žåšå²ã®èäœãéœæ§æèŠãåãããããããå
ç«é»é¡ã«ããæ€çŽ¢ãããšã空èåãããªãœãœãŒã èã«æŽ»æ§åã«ã«ãã€ã³å±åšãã¿ããããåŸã£ãŠãèè¡åŸã®CA-1ãã¥ãŒãã³ã«ç¹ç°çã«muã«ã«ãã€ã³ã®æŽ»æ§åãçããããšãåã³in vivoã§ã®æŽ»æ§åmuã«ã«ãã€ã³ã®åºè³ªã¯ãªãœãœãŒã èã®èèçœããã®é¢é£èçœã§ããããšã瀺åããããããã«ãæã«ããã·ã³Bæäœãçšããå
ç«æè²ãè¡ããšãäžéæ§ã®èè¡åŸã«ã¯CA-1以å€ã®æµ·éŠ¬ãã¥ãŒãã³ã¯ãªãœãœãŒã å
ã§ã®æè²æ§ã®å¢å ã瀺ããã®ã§ããã®ã«å¯ŸããCA-1ãã¥ãŒãã³ã¯ç¹ç°çã«ãªãœãœãŒã å€ãžã®ã«ããã·ã³ã®æŸåºã瀺ããã以äžãããCA-1ãã¥ãŒãã³ã«ãããŠç¹ç°çã«æŽ»æ§åãããmuã«ã«ãã€ã³ã¯ããªãœãœãŒã èèçœãéå®å解ããçµæèã®æè£ãããããã«ããã·ã³BããªãœãœãŒã å€ã«æŒåºãããã®ãšæšå®ããããããã§ãã«ããã·ã³Bã®ç¹ç°çæ®æè¬ã§ããCA-074ãèè¡è² è·åŸã«æäžãããšãCA-1é åã®çŽ2/3ã®ãã¥ãŒãã³ã¯è»œåºŠã®èè¡æ§å€åã瀺ããã®ã®é
çºçç¥çµçŽ°èæ»ã¯å
ããŠãããç 究課é¡/é åçªå·:09267215, ç 究æé(幎床):1997åºå
žïŒç 究課é¡ãã«ã«ãã€ã³ãšã«ããã·ã³ã®åæ
ããèŠãéé·é¡ã®èè¡æ§ç¥çµçŽ°èæ»ã®ç
æ
ãšæ²»ç ã課é¡çªå·09267215ïŒKAKENïŒç§åŠç 究費å©æäºæ¥ããŒã¿ããŒã¹ïŒåœç«æ
å ±åŠç 究æïŒïŒ ïŒhttps://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09267215/ïŒãå å·¥ããŠäœ
è³è «çã«ããã现èéæ¥çå å(ã«ãããªã³)ã®ç 究
é沢倧åŠå»åŠéšã«ãããªã³ã¯ã«ã«ã·ãŠã äŸåæ§ã®çŽ°èæ¥çååã§ãçµç¹ã®åœ¢æ
圢æãè
«ç圢æã«ãããŠéèŠãªåœ¹å²ãæãããšãããŠãããæ¬ç 究ã«ãããŠã¯ãé«èè
«ã®çºçã«éãã«ãããªã³ãã©ã®ãããªåœ¹å²ãæãããŠããããæããã«ããããã«ãé«èè
«ãšãã®çºçæ¯å°ã§ããã¯ã¢è絚æ¯ã«ã€ããŠãçååŠçãªãã³ã«å
ç«çµç¹ååŠçãªç 究ãè¡ã£ãã察象ã¯3äŸã®ã¯ã¢è絚æ¯ãš31äŸã®é«èè
«ã§ãããåŸè
ã®å
èš³ã¯åè现èå(syncytial type)ã11äŸã移è¡å(transitional type)ã12äŸããã³ç·ç¶èœçŽ°èå(fibroblastic type)ã8äŸã§ãããã¢ãã¯ã-ãã«æäœã¯ããäžç®åã«ãããªã³(Eåã«ãããªã³)ã«ç¹ç°çã«åå¿ããHECDãŒ1ãçšããããŠãšã¹ã¿ã³ããããã£ã³ã°ã§ã¯ãã¯ã¢è絚æ¯ããã³åè现èåãšç§»è¡åã®é«èè
«ã«ãããŠå
šäŸã«ååéçŽ124KDã®Eåã«ãããªã³ãæ€åºãããã®ã«å¯Ÿããç·ç¶èœçŽ°èåã§ã¯1äŸãæ€åºãããªãã£ããå
ç«çµç¹ååŠçã«ã¯ãã¯ã¢è絚æ¯ã§ã¯ã¯ã¢è现èå±€(arachnoid cell layer)ã现èéç°éš(cap cell cluster)ããã³äžè¯éš(central core)ã®ã¯ã¢è现èã«Eåã«ãããªã³ã®çºçŸãã¿ãããããç·ç¶æ§è¢«è(fibrous capsule)ã§ã¯ã¿ãããªãã£ããäžæ¹ãé«èè
«ã«ãããŠã¯ãåè现èåãšç§»è¡åã®åèäœã圢æããéšåã«Eåã«ãããªã³ã®çºçŸã匷ãã¿ããããã移è¡åã®æç¶é
å(stream)ã圢æããéšåã§ã¯åŒ±ããç·ç¶èœçŽ°èåã§ã¯ã¿ãããªãã£ããå
ç«é»é¡ã«ããæ€çŽ¢ã«ãããŠã¯ãã¯ã¢è絚æ¯ã§ã¯Eåã«ãããªã³ã¯ãé£æ¥ããã¯ã¢è现èéã«æç¹ç¶ã«åéããŠååšããŠããã®ã«å¯Ÿããé«èè
«ã§ã¯æ¥çè£
眮ãå«ã现èéã®ã»ãŒå
šåã«ååžããããããã®çºçŸéã¯å¢å ããŠããã以äžã®çµæãããã«ãããªã³ã®çºçŸæ§åŒã®å·®ç°ãé«èè
«ã®çµç¹åŠçå€æ§æ§ãšå¯æ¥ã«é¢é£ããŠããããšãããã³è
«çåã«äŒŽãã«ãããªã³ã®ååžãçºçŸéã«å€åãçããããšã瀺åããããç 究課é¡/é åçªå·:02670624, ç 究æé(幎床):1990åºå
žïŒç 究課é¡ãè³è
«çã«ããã现èéæ¥çå å(ã«ãããªã³)ã®ç 究ã課é¡çªå·02670624ïŒKAKENïŒç§åŠç 究費å©æäºæ¥ããŒã¿ããŒã¹ïŒåœç«æ
å ±åŠç 究æïŒïŒ ïŒhttps://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-02670624/ïŒãå å·¥ããŠäœ
å®éšçè³è¡ç®¡æ£çž®ãæ¹èµ·ããäžèç现èå£æ»ã®ç æ ãšæ²»ç
é沢倧åŠå»åŠéšä»å±ç
é¢ã»è³ç¥çµå€ç§è³è¡ç®¡æ£çž®ã¯åºæ¿ç©è³ªã«ããè¡ç®¡ã®æ©èœçåçž®(第1çž), äžèç现èå£æ»ã«ããè¡ç®¡ã®éº»çºæ§æ¡åŒµ(第2çž)ããã³å
èè¥åã«ããè¡ç®¡å
è
ã®åœ¢æ
åŠçç容(第3çž)ã®3çžæ§å€åã瀺ãã. å³ã¡, èŽæ»çãªè³è¡ç®¡æ£çž®ãå䜵ããã¯ã¢èäžåºè¡, é«èçããã³è¢«æ®»åºè¡æè¡ã®èš10çäŸããæ¡åãããæ£çž®è¡ç®¡ãå
é¡ç, é»é¡çã«æ€çŽ¢ããçµæ.(1)èŠåºäžéšããšã«laterl hypo-thalamicã«èè¡æ§å€åãã¿ããã. ãŸã, ããèäžè
ã®å°è¡ç®¡ããå€æ°ã®çç现èãè¡æ¶²ç©è³ªãæŒåºããŠãã.(2)è³è¡ç®¡æ£çž®ã¯åå ã®åŠäœãåããåæ§ãªè¡ç®¡ç
å€ãæ¹èµ·ãã.(3)å
èã¯å
é¡çã«ã¯å
ç®äžå±€ã®æ°Žè
«ãšçµåçµç¹ã®å¢æ®ã瀺ã, è¡ç®¡å
è
ã圢æ
åŠçã«ç容ããŠãã. é»é¡çã«ã¯å
ç®çŽ°èéã«open juncetonãã¿ãã, å
ç®äžå±€ã§ã¯myofibroblastãå¢æ®ãå€éã®çµåçµç¹ãåºåºèæ§ç©è³ªãç£çããŠãã.(4)äžèã¯å
é¡çã«ç现èã®å¥œé
žæ§ã®ååºå£æ»ã«ãã絶察æ°ãæžå°ã, è¡ç®¡å£ã®è²èåãšè¡ç®¡å
è
ã®æ¡åŒµãã¿ããã.(5)é»é¡çã«ã¯äžèç¯çŽ°èå£æ»ã®åºæ¬çç¹åŸŽã¯çç·çšã®è解ã§ãã, ãããã¯åŸ®çŽ°é¡ç²ç¶ç©è³ªã«çœ®æããŠãã.(6)现èå
åšå®€ã¯è
«å€§ããç²é¢å°èäœãšç³žç²äœã®ã¿ãæ®åã, èäœå
ã«ã¯å€æ°ã®ã©ã€ãœãŸãŒã³ãã¿ããã.(7)现èééã§ã¯åºåºèæ§ç©è³ªã®å¢å ãšå€éã®çŽ°èæ®ããã¿ããã. ããã«, èŠäº€å槜ã«è¡æ¶²ããšããããªã³ã泚å
¥ããŠè£œäœããå®éšçè³è¡ç®¡æ£çž®ã¢ãã«ç¬30é ããæ¡åãããæ£çž®è¡ç®¡ãçµç¹åŠçã«æ€çŽ¢ããçµæ, (1)ç¬ã®èŠäº€å槜ã«1CC/kgã®è¡æ¶²ã泚å
¥ããŠãèšåºåæ€äŸã«äŒŒãäžèç现èå£æ»ãäœè£œãåŸãªãã£ã.(2)ããã, 0.2mg/kgã®ãšããããªã³ã泚å
¥ãããš, å®éš2æ¥ç®ãã90æ¥ç®ã«ãããŠäžè现èå£æ»ã芳å¯ããã.(3)äžè现èå£æ»ã¯èŠåºäžéšã®è»åå·£ãšã¯ã¢èäžè
ã®å°è¡ç®¡ã®ééæ§äº¢é²ãå䜵ããç¬ã§é¡èã§ãã£ã.(4)ãšããããªã³ã®èŠäº€å槜å
泚å
¥ã«ããäœè£œãããå®éšçè³è¡ç®¡æ£çž®ã¯èšåºåæ€äŸã«ãã䌌ãäžèç现èå£æ»ãããã.Myonecrosis following cerebral vasospasm associated with subarachnoid hemorrhage, meningitsis and trans-sylvian surgery was ultrastructurally studied. The basic feature of myonecrosis was dissolution of myofilaments with resultant fine granular or filamentous material. The disintegrating cytoplasm often contained numerous glycogen granules, dense bodies, autophagic vacuoles and myelin-like membranous bodies. A well-developed sarcoplasmic reticulum was preserved despite myofilament dissolution, while mitochondria showed marked swelling. The nuclei showed either dilution of chromatin or pyknotic change. The basal lamina was remarkably thickened and maintained an irregular outline of the necrotic smooth muscle cells. Enlarged intercellular space contained abundant cellular debris, vesicular structures and connective tissue fibers. Furthermore, myonecrosis following the injection of epinephrine into the canine chiasmatic cistern was studied. Microscopically, the circle of Willis showed coagulation necrosis and fibrosis of the media. The fine structure of myonecrosis was characterized by six dynamic chenges of vacuolation, dissolution of myofilaments, focal cytoplasmic necrosis, fragmentation, coagulation necrosis and intercellular fibrosis. Despite a simple experimental procedure, the present models disclosed myonecrosis with a marked similarity to humans and contained all of the previously reported ultrstructural features of experimental myonecrosis.ç 究課é¡/é åçªå·:60570665, ç 究æé(幎床):1985 â 1987åºå
žïŒç 究課é¡ãå®éšçè³è¡ç®¡æ£çž®ãæ¹èµ·ããäžèç现èå£æ»ã®ç
æ
ãšæ²»çã課é¡çªå·60570665ïŒKAKENïŒç§åŠç 究費å©æäºæ¥ããŒã¿ããŒã¹ïŒåœç«æ
å ±åŠç 究æïŒïŒ ïŒhttps://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-60570665/605706651987kenkyu_seika_hokoku_gaiyo/ïŒãå å·¥ããŠäœ
Pç³èçœã®è¡æ¶²ãŒè³é¢éåã³è³è «çã®çŽ°èèééæ§ã«å¯Ÿããå¹æ
Pç³èçœãè³å
æ¯çŽ°è¡ç®¡å
ç®çŽ°èåã³è³è
«çã®çŽ°èèééæ§ã«åãŒã圱é¿ã«ã€ããŠãè¬ç©åæ
åŠçãçååŠçåã³å
ç«çµç¹ååŠçãªæ€çŽ¢ãè¡ã£ããã©ããã®è³ã«15äžåã®9Lã°ãªãªãŒã现èãå®äœè³çã«ç§»æ€ããåŸ2é±éç®ã«,1)ã©ãžãªã¢ã€ãœããŒãã§ã©ãã«ããè¬å€ãé åèå
ã«æ³šå
¥ã,5ç§éã§ã®è³å
åã³è
«çå
ãžã®ç§»è¡ã液äœã·ã³ãã¬ãŒã·ã§ã³ã«ãŠã³ã¿ãŒã«ãã枬å®ã,Oldendorfãã®æ¹æ³ã«ãã解æãã.ããã«,2)è¬å€ã现èå€ã«æåºããããšã§ç现èã®å€å€è¬å€èæ§ã«é¢äžããP-ç³èçœã®æç¡ã,C-219ã¢ãã¯ããŒãã«æäœãçšããŠè³å
æ¯çŽ°è¡ç®¡,è
«çå
è¡ç®¡åã³è
«ç现èèã«ãããŠå
ç«çµç¹ååŠçã«æ€çŽ¢ã,3)ãããã®è¶
埮æ§é ãšã®é¢é£ãæ€çŽ¢ãã.ãã®çµæ,1)è¡æ¶²-è³é¢éã移è¡ããªãã¯ãã®ã·ã¥ã¯ããŒã¹ã¯9Lã°ãªãªãŒãå
ã«è³å
ãžã®åã蟌ã¿ã®5å移è¡ãã.MCNUãš5-FU,ã¢ããªã¢ãã€ã·ã³ã¯ã·ã¥ã¯ããŒã¹ãšåæ§ã«æ£åžžè³å
ãžã¯ã»ãšãã©ç§»è¡ããªãã£ãã,ACNUã¯ã·ã¥ã¯ããŒã¹ããã¯ææã«å€ã移è¡ãã.MCNUãšã¢ããªã¢ãã€ã·ã³ã¯ã³ã³ãããŒã«ã§ããã·ã¥ã¯ããŒã¹ãšåæ§,è
«çå
ã«ã¯ååã«åã蟌ãŸããã,è
«ç现èå
ãžã¯åã蟌ãŸããªãã£ããäžæ¹,ACNUãš5-FUã¯è
«ç现èå
ã«ãèæã«åã蟌ãŸãã.5-FUã®å¹é€9Lã°ãªãªãŒã现èå
ãžã®ç§»è¡ã¯,ATPé»å®³å€ã4âã®å¹é€æ¶²äžã§èããæžå°ãã.2)è³å
æ¯çŽ°è¡ç®¡ã®å
ç®çŽ°èãš9Lã°ãªãªãŒãã®è
«ç现èèã§ã¯å
ç«çµç¹ååŠçã«P-ç³èçœã®çºçŸãã¿ãããã,è
«çå
è¡ç®¡ã®å
ç®çŽ°èã«ã¯ã¿ãããªãã£ã.3)è
«çå
è¡ç®¡ã®å
ç®çŽ°èã«ã¯é»é¡çã«å€æ°ã®çªåœ¢æãå
ç®çŽ°èã®è
«å€§,åã³å
ç®çŽ°èééã®é倧çã芳å¯ããã.以äžãã,MCNUã5-FU,ã¢ããªã¢ãã€ã·ã³ã®è³å
ãžã®ç§»è¡ã®ã¿ãªãã,MCNUãã¢ããªã¢ãã€ã·ã³ã®9Lã°ãªãªãŒã现èå
ãžã®ç§»è¡ã¯,ããããè³å
æ¯çŽ°è¡ç®¡å
ç®çŽ°èèãšè
«ç现èèã«çºçŸããP-ç³èçœã«ãã现èå€æåºã®çºå¶éãããŠãããã®ãšæšå®ããã.Two weeks after the inoculation of 1.5x10^5 of 9L glioma cells into the rat brain, the transfer of radiolabelled drugs into the brain and the experimental 9L glioma during the first cerebral circulation,was measured with a liquid scintilation counter and analyzed by the method of Oldendorf. The expression of P-glycoprotein, which is known to be associated with the efflux of drugs, was also studied, using anti-P-glycoprotein monoclonal antibody: C-219. Furthermore, the ultrastructure of brain capillaries, tumor vessels and glioma cells was studied by conventional and immuno-electron microscopy. Sucrose (control), the transport of which through the blood-brain barrier is known to be saturable, accumulated to 5 fold higher levels in the tumor relative to brain. MCNU (ranimustine: methyl 6-[3-(2-chloroethyl-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside), 5-FU (5-fluorouracil) and doxorubicin (Adriamycin) showed quite little accumulation into the normal brain, whereas ACNU (nimustine: 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride) showed an increased accumulation. MCNU and doxorubicin showed negligible accumulation in the glioma cells despite diffusion into the tumor interstitial space. In contrast, ACNU and 5-FU showed an increased accumulation in tumor cells. The transfer of 5-FU into the cultured 9L glioma cells was decreased by ATP inhibitors or by low temperature. Although both brain capillary endothelial cells and glioma cell membranes were immunohistochemically positive for P-glycoprotein, the tumor vasculature showed low expression of P-glycoprotein. The endothelial cells of tumor vessels ultrastructurally showed increased fenestrations, swelling and disrupted junctions. Accordingly, it is suggested that hydrophilic drugs such as doxorubicin, being pumped out by P-glycoprotein, do not accumulate in 9L glioma as do other lipophilic drugs such as ACNU, or 5-FU associated with the carrier-mediated mechanism.ç 究課é¡/é åçªå·:03454347, ç 究æé(幎床):1991-1992ç 究æ©é¢: é沢倧åŠå»åŠéšåºå
žïŒãPç³èçœã®è¡æ¶²ãŒè³é¢éåã³è³è
«çã®çŽ°èèééæ§ã«å¯Ÿããå¹æãç 究ææå ±åæžã課é¡çªå·03454347(KAKENïŒç§åŠç 究費å©æäºæ¥ããŒã¿ããŒã¹ïŒåœç«æ
å ±åŠç 究æïŒ)ãããæ¬æããŒã¿ã¯èè
çå ±åæžããäœ
äžéæ§è³èè¡åŸã®ãµã«æµ·éŠ¬ã«ãããéºäŒåãèçœããã³ç¥çµå¹¹çŽ°èã®çºçŸå€å
ãã¥ãŒãã³æ°çã«é¢å¿ãæã€ç 究è
ã®å€§éšåããã£æ¯ã察象ãšããŠããäžççç¶æ³ã®äžã§ãç³è«è
ã¯è³èè¡ãµã«ãçšããŠããã£æ¯é¡ã®ãã¥ãŒãã³æ°çãšéé·é¡ã®ãããšã®éã«ã¯èæãªå·®ç°ãããããšãæããã«ããã1)ãã£æ¯é¡ã§å ±åãããéããè³èè¡è² è·ã¯æäœãµã«æµ·éŠ¬ã®ç¥çµç³»åé§çŽ°è(NPCs)ãå¢å ãããããããããã®å¢å 床ã¯ãã£æ¯é¡ã®ããã1/10ã§ãããNPCsããç¥çµçŽ°èãžã®åå床ã¯ãã£æ¯é¡ã®ããã1/15ã§ããã2)ãŸãããã£æ¯é¡ãšã¯ç°ãªããµã«ã®åŽè³å®€äžåž¯(SVZ)ã®NPCsã¯æµ·éŠ¬CA1ã«ãããŠç¥çµçŽ°èã«ååããããšã¯çç¡ã§ãã£ããããªãã¡ããã£æ¯é¡ã®ããŒã¿ã«åºã¥ããè³å®€äžåž¯ã®NPCsãçš®ã
ã®æ é€å åçã«ãã賊掻ããŠæµ·éŠ¬CA1ã®ãã¥ãŒãã³æ°çãä¿ãããšã¯éé·é¡ã«ãããŠã¯ããããŠãããããã3)次ã«ããã£æ¯é¡ãšãµã«ã®å
åšæ§ã·ã°ãã«ã®å·®ç°ãæããã«ãããããªãã¡ããã£æ¯é¡ã®NPCsããã³ãã¥ãŒãã³åé§çŽ°èã¯èå
è³ã®ãã¥ãŒãã³æ°çãä¿ã転åå åã§ããPax6ãšEmx2ããã³Ngn2ãçºçŸããŠããããããããµã«ã®SVZã§ã¯ãããã®è»¢åå åã¯NPCsã®æ®µéã§çºçŸããŠããã®ã¿ã§ããã¥ãŒãã³åé§çŽ°èã«ãããŠã¯ãããã®è»¢åå åã®çºçŸã¯ã¿ããããSox1ãNgn1ãDlx1/5ãOlig3ããã³Nkx2.2ã®çºçŸãã¿ãããã4)èè¡åŸã®ãã¥ãŒãã³æ°çãèŠããããµã«æµ·éŠ¬ã«ãããŠã¯ãNPCsã¯è³å®€äžåž¯ã§ã¯ãªãé¡ç²äžå±€(SGZ)ã®è¡ç®¡ã®å€èã«ç±æ¥ããŠãããããããSGZã®è¡ç®¡ããã·ã§ã¯CA1ãšã¯å¯Ÿç
§çã«æé·å åã§ããBDNFãæ¥çå åã§ããPSA-NCAMã«å¯ãã§ããã5)ãµã«åŽè³å®€äžåž¯ããã³å
çã«ãããŠãè³èè¡è² è·ã«ãã£ãŠNPCsãå¢å ããŠããããããããæ°ç®è³ªãç·ç¶äœãžãšéèµ°ããŠç¥çµçŽ°èã«ååããããšã¯äŸå€çã§ããã£æ¯é¡ã§ã®å ±åãšã¯ããããŠå¯Ÿç
§çã§ãã£ããThe followings are main findings of the past three years, using a model of cerebral injury-global ischemia.1)We found that ischemia can increase the number of NPC in adult monkey hippocampus similarly to the rodent brain, but the monkey response was much lower than the rodent response-10 times in quantity, and more importantly-15 times in ability to produce neurons (neuronal differentiation) (Mol Cell Neurosci 23:292-301,2003).2)Further, monkey NPC were unable to replace any neurons in the ischemia-vulnerable CA1 sector (Glia 42;209-224,2003), which suggests that they cannot mediate a clinically-significant effect without an external influence.3)Recently, we have identified potential molecular explanation for this discrepancy between rodent and monkey NPC-while rodent NPC in CA1 sector express the developmental transcription factors Pax6,Emx2 and Ngn2 that can promote neurogenesis, monkey NPC in CA1 did not express these proteins.4)Importantly, we have identified a vascular niche around the adventitia of blood vessels that can promote neurogenesis in monkey dentate gyrus but not in CA1 sector (Hippocampus 14:861-875,2004).5)Lastly, we were the first to describe postischemic NPC upregulation in SVZ of the lateral ventricle, also in the olfactory bulb, and a limited neuronal production in the postischemic monkey neocortex and striatum (J Neurosci Res 81:776-788,2005).6)Thus, the applicant\u27s group has investigated all major regions in the primate telencephalon with respect to postischemic neurogenesis.ç 究課é¡/é åçªå·:15390432, ç 究æé(幎床):2003-2005ç 究æ©é¢: é沢倧åŠå€§åŠé¢å»åŠç³»ç 究ç§åºå
žïŒãäžéæ§è³èè¡åŸã®ãµã«æµ·éŠ¬ã«ãããéºäŒåãèçœããã³ç¥çµå¹¹çŽ°èã®çºçŸå€åãç 究ææå ±åæžã課é¡çªå·15390432 (KAKENïŒç§åŠç 究費å©æäºæ¥ããŒã¿ããŒã¹ïŒåœç«æ
å ±åŠç 究æïŒ)ãããæ¬æããŒã¿ã¯èè
çå ±åæžããäœ
Ðxpression of Transcriptional Factor SOX2 in Populations of Cortical Progenitors in Human Fetal Telencephalon
Cerebral cortex Пf mammals is mainly generated during the embryonic period by stem cells and their derivative progenitors in the palium of the developing telencephalon. Various genes in complex interactions are involved in the processes of differentiation of the cerebral neurons. Transcriotional factor Sox2 plays a key role for self renewing and sustaining multipotency of embryonic neural stem/progenitor cells. Data about the expression and function of Sox2 in human fetal brain are insufficient and controversial.In the present sudy tissue samples of spontaneously aborted human fetuses aged between 12th to 28th gestational weeks (g. w.) were examined by a standard histological and immunohistochemical technique for paraffin sections. Sox2 expression was followed in the zones of cellular proliferation and migration in the occipital lobe of human fetal telencephalon mainly during 17th g. w. Within ventricular and outer subventricular zones we detected similar amount approximately 45% Sox2+ cells, whereas in the intermediate zone, cortical plate and marginal zone expression of Sox2 was not found.The data obtained on the location and expression dynamics of Sox2 contribute to a more complete understanding of neural stem/progenitor cell biology during embryonic neurogenesis in the human cerebral cortex
Quantity and Distribution of Proliferating Cells in the Juvenile and Adult Primate Spinal Cord
ÃÅultipotent progenitors exist in the adult mam- malian central nervous system, capable of producing both neurons and glia. Their proliferation in the spi- nal cord is limited. Generation of putative stem/pro- genitor cells has been reported in intact and injured spinal cord of rodents and in a limited number in monkeys with a spinal injury, but not in intact spi- nal cord in vivo. We recently reported de novo gener- ated cells in the intact spinal cord of macaque mon- keys. Here we extend these findings by showing data of intact juvenile and neonatal monkey spinal cord. We used bromodeoxyuridine (BrdU) to label the de novo generated cells in the experimental animals and stud- ied their quantity and distribution at different time- points after the BrdU infusion. As expected, we found a significant elevation of the BrdU-labeled cells at neo- natal stage. However, there was no difference between juvenile and adult stages. These results suggest that the survival of newly born cells in the intact primate spinal cord does not change after juvenile stage and this could be used to further study repair mechanisms in adult primate spinal cord
Phenotype of De Novo Generated Cells in the Spinal Cord of Adult Macaque Monkeys
Neuronal stem and progenitor cells exist in the spinal cord of sexually mature mammals. ÃhÃ¥y play an important role during repaining processes after in- jury, but their proliferation and differentiation are limited. In the present study we used the proliferative marker bromodeoxyuridine (BrdU) for a short (2 h) and three longer survival periods (2, 5 and 10 weeks) to investigate the quantity, topography and fate of de novo generated cells in intact spinal cord of adult pri- mates (macaque monkeys). We applied as well single or in combinations markers for mesenchymal cells or/ and neuronal stem/progenitor cells to demonstrate the phenotype of the proliferating cells. We found that af- ter the short period of BrdU application (2 h) the num- ber of BrdU+ cells is significantly elevated only in the cervical segments. Most of the cells in the ependymal layer are immunopositive for Vimentin or/and Nestin. This is an indice for their cellular belonging. A con- siderable number of Vimentin+ cells of the ependy- mal layer form long characteristic processes directed to underlying blood capillaries. Ãhis indicates their participation as a component of the ependymal cellu- lar niche. The presence of BrdU+/Nestin+ cells in the central canal surrounding zone confirms the existence of dividing neuronal stem/progenitor cells cells in the spinal cord of adult primates
- âŠ