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Volume 174 (1994)
- Issue 4 Pages 305-
- Issue 3 Pages 181-
- Issue 2 Pages 95-
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Volume 174, Issue 3
Displaying 1-12 of 12 articles from this issue
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ARATA SUZUKI, SACHIO TAKASHIMA, MASASHI MIZUGUCHI, MITSUHIRO KATO, TAT ...1994 Volume 174 Issue 3 Pages 181-187
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSSUZUKI, A., TAKASHIMA, S., MIZUGUCHI, M., KATO, M., KUNISHITA, T. and TABIRA, T. High Expression on Kunitz-Type Protease Inhibitor-Containing Substances in the Cerebral Vessels of Patients with Down Syndrome. Tohoku J. Exp. Med., 1994, 174 (3), 181-187 - Down syndrome (DS) brains, from 19 gestational weeks to 50 years of age were studied by immunohistochemical methods with a polyclonal antibody against synthetic peptide comprising part of the Kunitz-type protease inhibitor (KPI) domain of Alzheimer disease amyloid precursor protein (APP), residues 301 to 323 of APP 770. In DS, positive KPI immunoreactivity was observed in early infancy and from child to adulthood on the tunica media of the arteries in the leptomeninges, cerebral cortex and white matter, but negative or little in controls. In DS with Alzheimer type dementia, KPI immunoreactivity in the arteries was reduced, but a gross granular reactivity was noted in neurons and glial cells. The high expression of KPI in DS vessels may be one of the predisposing factors to vascular diseases and amyloid deposition associated with DS.View full abstractDownload PDF (1844K) -
SHU-ICHI IKEDA, TAKAHIKO TOKUDA, NOBUO YANAGISAWA, FUYUKI KAMETANI, TO ...1994 Volume 174 Issue 3 Pages 189-198
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSIKEDA, S., TOKUDA, T., YANAGISAWA, N., KAMETANI, F., OHSHIMA, T. and ALLSOP, D. Variability of β-Amyloid Protein Deposited Lesions in Down's Syndrome Brains. Tohoku J. Exp. Med., 1994, 174 (3), 189-198-An immunohistochemical study was carried out on the brains of 7 adult Down's syndrome cases (ages 31 to 62) using antibodies to β-protein, β-amyloid protein precursor and tau-protein. Variable forms of β-protein deposited lesions (including senile plaques and cerebrovascular amyloidosis) were observed in extensive areas of the neocortex of all cases and coexistence of both β-protein amyloid fibrils and β-amyloid protein precursors was also seen in some of these lesions. Moreover, 3 cases at an advanced stage showed a few plaque-like lesions with β-protein immunoreactivity in the white matter. The following temporal morphological change is suggested for the pathogenesis of Alzheimer's disease: senile plaque undergo sequential structural changes and β-protein amyloid deposits in the form of “early plaque” precede the development of tau-immunoreactive neurofibrillary degeneration.View full abstractDownload PDF (2967K) -
KATSUYA URAKAMI, AKITSUGU OKADA, KOUSAKU OHNO, NOBUYA KITAGUCHI, SEIGO ...1994 Volume 174 Issue 3 Pages 199-207
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSURAKAMI, K., OKADA, A., OHNO, K., KITAGUCHI, N., TANAKA, S., NAKAMURA, S. and TAKAHASHI, K. Amyloid Beta Protein Precursor with Kunitz-Type Protease Inhibitor Domains (APPI) in Cerebrospinal Fluid and APPI mRNAs in Cultured Skin Fibroblasts of Patients with Alzheimer's Disease. Tohoku J. Exp. Med., 1994, 174 (3), 199-207 - We studied amyloid beta protein precursor with Kunitz-type protease ihibitor domains (APPI) concentration in cerebrospinal fluid (CSF) and APPI mRNA in skin fibroblast in Alzheimer's disease (AD). The subjects consisted of AD, cerebrovascular dementia (VD) and age-matched controls. We measured the APPI concentration in the CSF by the trypsin antibody sandwich ELISA. APPI mRNA was examined by the RT-PCR tegchnique. The CSF APPI concentration in AD was significantly higher than that of VD and controls. The CSF APPI concentration in AD was high in the initial stage of dementia and decreased during the course. The expression of APPI mRNA in skin fibroblasts in AD was also significantly higher than that of VD and controls. These results suggest that measurements of APPI levels in CSF and APPI mRNA in skin fibroblasts may be useful for early diagnosis of AD.View full abstractDownload PDF (733K) -
KAYOKO KINBARA, HIROSHI KITAGAKI, TADATOSHI KINOUCHI, MASAMICHI OKANO, ...1994 Volume 174 Issue 3 Pages 209-216
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKINBARA, K., KITAGAKI, H., KINOUCHI, T., OKANO, M., SORIMACHI, H., ISHIURA, S. and SUZUKI, K. Processing and Secretion of Alzheimers's Disease Amyloid Precursor Protein. Tohoku J. Exp. Med., 1994, 174 (3), 209-216 - We studied in vivo expression and in vitro secretion of the Alzheimer's disease amyloid precursor protein (APP). The results indicate that secretion of APP is mediated by PKC and the initial step of the processing may occur in the acidic secretooy granules of the glial cells. Our results suggest that a metabolic switch of APP in neural cells is critical in amyloid deposition.View full abstractDownload PDF (1002K) -
STEVEN G. YOUNKIN1994 Volume 174 Issue 3 Pages 217-223
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSYOUNKIN, S.G. The Amyloid β Protein Precursor Mutations Linked to Familial Alzheimer's Desease Alter Processing in a Way That Fosters Amyloid Deposition. Tohoku J. Exp. Med., 1994, 174 (3), 217-223 - Normal processing of the amyloid β protein precursor (BAPP) results in secretion of a soluble 4kD protein essentially identical to the amyloid β protein (Aβ) that forms insoluble fibrillar deposits in Alzheimer's disease (AD). Strong evidence that amyloid deposition plays a critical role in the development of AD has come from the identification of familial AD (FAD) kinderds in which the AD phenotype cosegregates with mutations in the βAPP gene that are located close to the NH2 or COON end of the Aβ peptide. The location of these mutations immediately suggests that they may cause AD by altering βAPP processing in a way that is amyloidogenic. In a previous study, we found that transfected cells expressing the NH2 side mutant secrete 6-fold more 4kD Aβ than those expressing wild type BAPP or COON side mutants. We have now shown that the mutations on the COON side of Aβ alter processing to increase secretion of the more amyloidogenic Aβ1-42 form which constitutes only a small percentage of the total 4kD Aβ produced. Thus our data show that all of the FAD-linked βAPP mutations alter βAPP processing in a way that increases the likelihood of amyloid formation.View full abstractDownload PDF (695K) -
TATSUHIDE KUNISHITA, SACHIYA IKEDA, WATARU ARAKI, TAKESHI TABIRA1994 Volume 174 Issue 3 Pages 225-239
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKUNISHITA, T., IKEDA, S., ARAKI, W. and TABIRA, T. The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line. Tohoku J. Exp. Med., 1994, 174 (3), 225-239-The effects of β-amyloid precursor protein (APP) overexpressing on cell metabolisms of cholinergic neuronal hybridoma cell line (SN49) were examined. The cells stably overexpressing APP contained higher amount of GTP binding protein Go and cytosolic inactive protein kinase Cε, and showed less Ca2+ influx through muscarinic acetylcholine receptor ml compared to original and mock cells which had been transfected with a vector alone. The contents of sn-1, 2-diacylglycerol and cycilc AMP were also reduced in the APP transfectants, although the similar changes were observed in the mock cells. These findings strongly suggest that the overexpression of APP affect the transient receptor-mediated ion channel and calcium-related cell metabolisms in neuronal cells.View full abstractDownload PDF (2007K) -
TOSHITAKA NABESHIMA, ATSUMI NITTA1994 Volume 174 Issue 3 Pages 241-249
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSNABESHIMA, T. and NITTA, A. Memory Impairment and Neuronal Dysfunction Induced by β-Amyloid Protein in Rats. Tohoku J. Exp. Med., 1994, 174 (3), 241-249 - Alzheimer's disease (AD) is characterized by the presence of senile plaques. The core of the plaque consists of β-amyloid protein. In AD patients, learning and memory are impaired with a concomitant loss of the cholinergic marker enzyme, choline acetyltransferase (ChAT). However, direct evidence that β-amyloid protein is related to the impairment of learning and memory has not been demonstrated. In this study, we investigated whether memory impairment and neuronal dysfunction were produced after 2 weeks continuous infusion of β-amyloid protein (3, 30 and 300pmol/day) into the cerebral ventricles in adult rats. To investigate the ability of learning and memory in β-amyloid proteintreated rats, water maze and passive avoidance tasks were carried out. The performance of both tasks in β-amyloid protein-treated rats was impaired. ChAT activity in the frontal cortex (3 and 30pmol/day) and hippocampus (300pmol/day) significantly decreased. These results suggest that β-amyloid protein is related to the impairment of learning and memory, and neurodegeneration, and that β-amyloid protein-treated rats could be used as an animal model for AD.View full abstractDownload PDF (1291K) -
HIROSHI MORI, KAZUHIRO ISHII, TAKAMI TOMIYAMA, YOSHIKO FURIYA, NARUHIK ...1994 Volume 174 Issue 3 Pages 251-262
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSMORI, H., ISHII, K., TOMIYAMA, T., FURIYA, Y., SAHARA, N., ASANO, S., ENDO, N., SHIRASAWA, T. and TAKIO, K. Racemization: Its Biological Significance in Neuropathogenesis of Alzheimer's Disease. Tohoku J. Exp. Med., 1994, 174 (3), 251-262 - Amyloid β protein (Aβ) in neuritic plaques of Alzheimer's disease has been found to be racemized and/or isomerized at their Asp residues. To elucidate the effect of racemization on the aggregation properties of Aβ, we synthesized three kinds of Aβ peptides in which D-Asp was substituted for L-Asp residues, i.e, normal Aβ1-40, [D-Asp7] Aβ1-40 and [D-Asp23] Aβ1-40. The aggregation and fibril formation of each peptide was examined by means of spectrofluorometry and electron microscopy. Of the three peptides, normal Aβ showed the gradual increase of aggregation while [D-Asp7] Aβ1-40 and [D-Asp23] Aβ1-40 showed more enhanced aggregation at the final stage when the fibril formations were detected in all peptides solutions by electron microscopy. A comparative immunohistochemical study by anti-racemized Aβ antibody and anti-Aβ1-42/43 antibody further showed the in vivo incorporation of D-Asp in senile plaques of Alzheimer's disease brains, which may be involved in plaque formation at the later stage than the deposition of the longer form of Aβ (Aβ1-42/43). Taken together with the recent accumulated evidence on the aggregation mechanisms of Aβ, the data presented here suggest that racemization may occur after the amyloid fibril formation but enhance the aggregation process by shifting the equilibrium of Aβ from the soluble form to the insoluble form in Alzheimer's disease.View full abstractDownload PDF (2387K) -
YOICHIRO KURODA, MASAHIRO KAWAHARA1994 Volume 174 Issue 3 Pages 263-268
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKURODA, Y. and KAWAHARA, M. Aggregation of Amyloid β-Protein and Its Neurotoxicity: Enhancement by Aluminum and Other Metals. Tohoku J. Exp. Med., 1994, 174 (3), 263-268 - The aggregation of amyloid β-protein has been suggested to enhance its neurotoxicity in cultured hippocampal neurons. We found that aluminum, an epidemiologic risk factor for Alzheimer's disease, promoted the aggregation of synthetic amyloid β-protein (β1-40) using immunoblotting and centrifugation. There were no significant changes by Ca or Mg. Other metals including Zn, Fe caused the small degree of aggregation compared to Al. Furthermore, β1-40 which was aggregated by aluminum was applied on cultured rat hippocampal neurons, and the characteristic deposition of amyloid fibrils was observed on cultured neurons. These results suggested that the degeneration of neurons and the deposition of amyloid β-protein were enhanced by aluminumView full abstractDownload PDF (722K) -
PATRICK L. MCGEER, ANDIS KLEGERIS, DOUGLAS G. WALKER, OSAMU YASUHARA, ...1994 Volume 174 Issue 3 Pages 269-277
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSMCGEER, P.L., KLEGERIS, A., WALKER, D.G., YASUHARA, O. and MCGEER, E.G. Pathological Proteins in Senile Plaques. Tohoku J. Exp. Med., 1994, 174 (3), 269-277 - The beta-amyloid protein deposits of Alzheimer disease, whether in diffuse or consoliated form, are an agglomeration of many extracellular proteins. At least 35 have been reported as components of senile plaques, most of which also occur in diffuse deposits. More than half of these proteins are directly associated with the immune system. Since diffuse deposits are believed to be the precursors of senile plaques, it is important to define the precise molecular events that lead to the transition. Diffuse deposits share with senile plaques the presence of opsonizing components of complement, the complement activators beta-amyloid protein, amyloid P, thrombin, and apolipoprotein E. However, senile plaques contain, in addition, dystrophic neurites, agglomerates of activated microglia, components of the membrane attack complex, and the inhibitors of the membrane attack complex, clusterin, protectin and vitronectin. Microglial cells are professional phagocytes which possess the respiratory burst apparatus when activated. It produces extracellular superoxide molecules which can then form additional toxic products such as hydrogen peroxide and hydroxyl free radicals. It has long been known that opsonized zymosan is a powerful activator of the respiratory burst system. We found this activation could be inhibited by antibodies to complement receptors in the nanomolar range. Dapsone and indomethacin, two antiinflammatory agents that may have therapeutic potential in Alzheimer disease, were weakly inhibitory (10-4M range). These data suggest that complement activation to a level where the membrane attack complex is generated, and respiratory burst toxins are produced, may underlie an autodestructive mechanism in Alzheimer disease, and further imply that intervention in this activation may have therapeutic possibilities.View full abstractDownload PDF (984K) -
HIROSHI KIMURA, IKUO TOOYAMA, PATRICK L. MCGEER1994 Volume 174 Issue 3 Pages 279-293
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSKIMURA, H, TOOYAMA, I. and MCGEER, P.L. Acidic FGF Expression in the Surroundings of Senile Plaques. Tohoku J. Exp. Med., 1994, 174 (3), 279-293 -Immunohistochemical examination of postmortem brain tissue of Alzheimer's disease revealed that acidic fibroblast growth factor (aFGF) was specifically expressed in a subpopulation of reactive astrocytes which were congregated at the margin of the senile plaque. Double immunostaining indicated that such upregulation of aFGF expression might be related to the presence of reactive microglia rather than β-amyloid protein deposits. Although, on the other hand, immunohistochemical staining for fibroblast growth factor receptor-1 occurred in some cortical neurons of Alzheimer's disease, the staining pattern did not differ from that in age-matched controls. Possible significance of aFGF-positive astrocytes in the surroundings of the senile plaque will be discussed in relation to receptor mediated or non-mediated mechanisms.View full abstractDownload PDF (2526K) -
HARUHIKO AKIYAMA1994 Volume 174 Issue 3 Pages 295-303
Published: 1994
Released on J-STAGE: August 31, 2006
JOURNAL FREE ACCESSAKIYAMA, H. Inflammatory Response in Alzheimer's Disease. Tohoku J. Exp. Med., 1994, 174 (3), 295-303 - Microglia belong to the mononuclear phagocyte system. They represent the brain resident tissue macrophages and function as the scavenger cells in brain. In Alzheimer's disease (AD), microglia become activated. Reactive microglia aggregate around senile plaque β-amyloid and neurofibrillary tangles. Heavy accumulation of these pathological debris in postmortem, however, indicates the failure or, at best, partial success of the removal. It is supposed that continued activation of microglia in these lesions elicits a persistent inflammatory response. In fact, activation fragments of the complement system have been detected in association with β-amyloid deposits and extracellular ghost tangles. Thrombin, a central serine protease of the coagulation pathway, is also deposited in these pathological debris. Both complements and thrombin could augment the biochemical, synthetic and phagocytic capacities of microglia. Microglia, in turn, might play a major role for the activation of complement and coagulation systems in brain. The available evidence strongly suggests a significant similarity between the chronic inflammation and the tissue response in AD lesions, supporting a notion that the inflammatory process is a part of Alzheimer pathology.View full abstractDownload PDF (1855K)
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