I Sakakibara

The University of Tokyo, Tokyo, Tokyo-to, Japan

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Publications (24)41.56 Total impact

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    ABSTRACT: To confirm the intracellular accumulation of amyloid beta-protein (Abeta), we carefully performed immunohistochemistry using brains of cynomolgus monkeys of various ages. Cortical neurones and their large neurites were immunostained with antibodies against Abeta in young monkey brains. In aged monkey brains, intracellular Abeta localized within cortical neurones; no clear association was found between the presence of intracellular Abeta and senile plaques (SPs). Interestingly, we did not observe Abeta-immunoreactive cortical neurones in brains fixed with neutral buffered formalin. Western blot analyses of microsomal and nerve ending fractions derived from the brains of young to aged monkeys revealed that intracellular Abeta generation changed with age. In the microsomal fraction, the amount of Abeta42 significantly increased in brains from older monkeys (>30 years of age), and the amount of Abeta43 significantly decreased with age in the microsomal fraction. The amount of Abeta40 remained the same regardless of age. Biochemical analyses also showed that intracellular levels of each of these Abeta molecules significantly increased with age in nerve ending fractions. As we previously observed that a similar accumulation of presenilin1, beta-amyloid precursor protein (APP) and APP C-terminal fragment cleaved by beta-secretase in the nerve ending fractions obtained from brains with SPs, the accumulation of intracellular Abeta in this fraction may be closely related to formation of spontaneous SPs with age. Taken together, these results suggest that intensive investigation of age-related changes in the nerve ending will contribute to a better understanding of the pathogenesis of age-related neurodegenerative disorders such as sporadic Alzheimer's disease.
    Neuropathology and Applied Neurobiology 05/2005; 31(2):170-80. · 4.84 Impact Factor
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    ABSTRACT: Localization of presenilin-2 (PS-2), a transmembrane protein implicated in early onset familial Alzheimer's disease, was examined in the brains of 30 cynomolgus monkeys aged 4 to 36 years. Anti-PS-2 antibody N20, which recognizes PS-2 amino acid residues 2-20, and anti-PS-2 antibody C20, which recognizes PS-2 amino acid residues 535-554, stained mainly the cytoplasm of large pyramidal neurons and large neurites. This finding was also confirmed by double immunohistochemical investigations using N20 or C20 and anti-NeuN antibody. In the brain of the oldest monkey, swollen neurites containing senile plaques were immunostained with C20, but not with N20. Western blot analyses of microsomal fractions isolated from the brains of three adult monkeys revealed that much less PS-2 was present compared to presenilin-1 (PS-1). Age-related assessment of PS-2 in brain homogenates from young and adult monkeys showed that PS-2 levels and PS-2 subcellular localization were unchanged with increasing age. Because PS-2 expression was much less robust than that of PS-1, we conclude that PS-2 mainly localizes to large neurons and does not show so drastic age-related changes as PS-1.
    Primates 08/2004; 45(3):167-75. · 1.29 Impact Factor
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    ABSTRACT: We characterized senile plaques (SPs) immunohistochemically in cynomolgus monkey brains and also examined age-related biochemical changes of Alzheimer's disease (AD)-associated proteins in these brains from monkeys of various ages. In the neocortex of aged monkeys (>20 years old), we found SPs but no neurofibrillary tangles (NFTs). Antibodies against beta-amyloid precursor protein (APP) or apolipoprotein E (ApoE) stained SPs; however, the pattern of immunostaining was different for the two antigens. APP was present only in swollen neurites, but ApoE was present throughout all parts of SPs. Western blot analysis revealed that the pattern of APP expression changed with age. Although full-length APP695 protein was mainly expressed in brains from young monkeys (4-years-old), the expression of full-length APP751 protein was increased in brains from older monkeys (>20 years old). Biochemical analyses also showed that levels of various AD-associated proteins increased significantly with age in nerve ending fractions. Both SP-associated (APP) and NFT-associated proteins (tau, activated glycogen synthase kinase 3beta, cyclin dependent kinase 5, p35, and p25) accumulated in the nerve ending fraction with increasing age; however, we found no NFTs or paired helical filaments of tau in aged cynomolgus monkey brains. This age-related accumulation of these proteins in the nerve ending fraction was similar to that observed in our laboratory previously for presenilin-1 (PS-1). The accumulation of these SP-associated proteins in this fraction may be a causal event in the spontaneous formation of SPs; thus, SPs may be formed initially in nerve endings. Taken together, these results suggest that intensive investigation of age-related changes in the nerve ending and in axonal transport will contribute to a better understanding of the pathogenesis of neurodegenerative disorders such as AD.
    Biochemical and Biophysical Research Communications 10/2003; 310(2):303-11. · 2.41 Impact Factor
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    ABSTRACT: A spontaneous T-cell-rich B-cell lymphoma (TCRBCL) occurred as a subcutaneous mass in the buccal region and enlarged submandibular lymph node in a 6-year-old female cynomolgus monkey (Macaca fascicularis). The constituent cells were examined by histology, immunohistochemistry and the double labeled-immunofluorescence method (dl-IF). Further, in situ hybridization (ISH) was employed to detect the gene expression of Epstein Barr virus (EBV). Histologically, the mass was comprised mainly of neoplastic large lymphoid cells and reactive small mononuclear cells. Immunohistochemically, the neoplastic large lymphoid cells were positive for CD20, CD79 alpha, MHC class II, and either IgG, IgM, or IgA. Polyclonal Ig production by the neoplastic large lymphoid cells was demonstrated by dl-IF, although IgG-positive ones predominated in number. On the other hand, most of the small mononuclear cells were positive for CD3 and were regarded as reactive T lymphocytes, while the remaining cells appeared to be histocytes or reactive B-cells. Transcripts of EBV gene were not demonstrated in these neoplastic or reactive cells by ISH. This is the first reported case of spontaneous TCRBCL in the cynomolgus monkey.
    Experimental Animals 08/2003; 52(4):339-44. · 1.46 Impact Factor
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    ABSTRACT: Age-related changes in PS-1 localization were examined in the brains of 22 cynomolgus monkeys ranging in age from embryonic day 87 to 35 years. In embryonic monkey brains, anti-PS-1 antibody N12, which recognizes the PS-1 N-terminal fragment (Ntf) and holo protein, stained immature neuronal cells. In juvenile monkeys, N12 stained large pyramidal neurons, cerebral neocortical neurons, and cerebellar Purkinje's cells. Cytoplasmic staining of these cells was granular in appearance. In aged monkeys, N12 stained neurons in all layers of the neocortex. In contrast, regardless of the age of the animals examined, M5, an anti-PS-1 antibody that specifically recognizes only the PS-1 C-terminal fragment (Ctf), stained neurons in all layers of the neocortex and neurons in the cerebellum. M5 also stained neuropil and white matter, and in aged monkeys, M5 stained swollen neurites of mature senile plaques. Age-related changes in PS-1 expression were further examined using Western blot analysis of mitochondrial, myelin, microsomal, nuclear, synaptosomal, and cytosol fractions isolated from 10 monkey brains ranging in age from embryonic day 87 to 32 years. In all brains, Ntf and Ctf were expressed most abundantly in the microsome fraction. The amount of PS-1 in the nuclear fraction dramatically increased with age. We conclude that the transport of PS-1 diminished with age and that PS-1 fragments accumulated in endoplasmic reticulum (ER) associated with the nuclear membrane.
    Brain Research 01/2002; 922(1):30-41. · 2.88 Impact Factor
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    ABSTRACT: Squamous cell carcinoma was observed in the oral cavity in a one-year-old male cynomolgus monkey. Histopathologically, the tumor consisted of various shaped cells and its assemblies infiltrated into the surrounding connective tissues. Although no obvious metaplastic keratinized cancer pearls were found in the tumor cells, the intercellular bridges were observed. Immunohistochemically, tumor cells were stained with anti-keratin, but not with anti-vimentin. On virological examinations, no papilloma virus antigen or Epstein-Barr Virus small mRNA could not be detected. Under the electron microscope, incomplete tonofibrils and desmosomes in the cytoplasm and microvillus of the cell membrane were observed, suggesting a malignancy or low differentiation of the tumor cells in the present case. This is the first case of squamous cell carcinoma observed in very young macaques, to our knowledge.
    Experimental Animals 08/2000; 49(3):225-8. · 1.46 Impact Factor
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    ABSTRACT: P. carinii infection in red-bellied tamarins (Saguinus labiatus), born and maintained in a laboratory breeding colony, was examined by histopathologic examination postmortem. P. carinii cysts were detected in 6 of 10 red-bellied tamarins examined, by using Grocott's, toluidine blue O and immunostaining with avidin-biotin complex using antisera for rat-, simian-, and human-P. carinii. The results obtained from the present studies imply that P. carinii may be an important pathogen in this species.
    Experimental Animals 02/1999; 48(1):55-7. · 1.46 Impact Factor
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    ABSTRACT: Senile plaques (SPs) and cerebral amyloid angiopathy (CAA), pathological hallmarks of Alzheimer's disease, have not been thoroughly investigated histopathologically in nonhuman primates. To determine the onset age and histopathological characteristics of SPs and CAA, we examined the brains of 64 cynomolgus monkeys (Macaca fascicularis) from 2 to 35 years old. Mature (classical and primitive) plaques appeared in 16 out of 25 monkeys that were >20 years old. Moreover, mature plaques were observed more frequently than diffuse plaques and were located in the temporal cortex of the superior or inferior gyri and amygdala. Diffuse plaques in contrast to mature plaques did not show definite tendencies in onset age and distribution. CAA appeared in more than 22-year-old monkeys in 10 out of 16 animals and was frequently observed in capillaries and often found adjoining mature plaques. During immunohistochemical examination, an antiserum for amyloid beta protein (A beta) 1-40 could detect all SPs, whereas a monoclonal antibody for A beta 8-17 could not detect any diffuse plaques and only one third of the primitive plaques. As for CAA, the polyclonal antiserum was more sensitive than the monoclonal antibody. The present study describes the histopathological features of SPs and CAA in old cynomolgus monkeys.
    Journal of Medical Primatology 11/1998; 27(5):244-52. · 1.11 Impact Factor
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    ABSTRACT: Spontaneous T cell leukemia was found in an African green monkey (Cercopithecus aethiops, AGM) naturally infected with simian T cell leukemia virus type I (STLV-I). The hematological features and the evidence for monoclonal integration of provirus DNA in the leukemic cells revealed that the leukemia was an ATL-like disease. The expression of surface markers on the leukemic cells indicated that they were defined as an activated CD8+ T cell subset. Together with the finding that seven in vitro spontaneously STLV-I-transformed cell lines were CD4-CD8+, it is likely that CD8+ T cells are transformed by STLV-I in AGMs, in contrast with human ATL. Finally, we assessed characteristics of the CD8 chains on these transformed cells. The result indicated that the leukemic cells expressed only the alpha chains but not the beta chains. However, in the case of in vitro-transformed cell lines the expression pattern of the CD8 chains varied in individual monkeys. Thus, STLV-I may preferentially transform CD8+ (both alphaalpha+ and alphabeta+) T cells in AGMs.
    AIDS Research and Human Retroviruses 03/1998; 14(4):367-71. · 2.71 Impact Factor
  • Aids Research and Human Retroviruses - AIDS RES HUM RETROVIRUS. 01/1998; 14(4):367-371.
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    ABSTRACT: In this study, we immunohistochemically examined the several constituents of senile plaques (SPs) and cerebral amyloid angiopathy (CAA) in aged cynomolgus monkeys. Apolipoprotein E (apoE) deposited in all mature plaques and CAA, and in half of the diffuse plaques. Alpha-1-antichymotripsin (alpha ACT) deposited in half of the mature plaques and in one third of the CAA. Amyloid precursor protein (APP), ubiquitin (Ub), and microtubule-associated protein-2 (MAP-2) accumulated in the swollen neurites of mature plaques. Glial fibrillary acidic protein (GFAP) was detected in the astrocytes and their processes surrounding the mature plaques. Tau was detected in neither the SPs nor CAA. Therefore, mature plaques involved extracellular A beta, apoE, and alpha ACT, and also astrocytes and swollen neurites. However, diffuse plaques involved only extracellular A beta and apoE. Since these features, except for tau, were consistent with those in humans, this animal model will be useful for studying the pathogenesis of cerebral amyloid deposition.
    Journal of Medical Primatology 09/1996; 25(4):294-300. · 1.11 Impact Factor
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    ABSTRACT: To investigate the role of apolipoprotein E (apo E) in amyloidoses of cynomolgus monkeys, the localization of apo E in cerebral amyloid, including senile plaques and cerebrovascular amyloid, and in islet amyloid was examined immunohistochemically. Mature types of senile plaques with amyloid deposits and cerebrovascular amyloid showed intense immunoreactivity to both antisera to apo E and amyloid beta protein (A beta). In contrast, diffuse plaques without obvious Congophilic amyloid showed weak immunoreactivity to antiserum to apo E, but intense reactivity to antiserum to A beta. In addition, the number of these apo E-positive diffuse plaques was small compared with that of A beta-positive plaques. On the other hand, diabetic islet amyloid that was negative with A beta, reacted intensely with antiserum to apo E. These findings suggest that apo E plays an important role in amyloid fibril formation in several types of amyloidoses.
    Experimental Animals 05/1996; 45(2):199-203. · 1.46 Impact Factor
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    ABSTRACT: Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) in the brains of five aged (20–26 years old) cynomolgus monkeys were investigated immunohistochemically using two monoclonal antibodies (anti-Aβ 40 (BA27) and anti-Aβ 42(43) (BC05)) that can differentiate the carboxyl termini of amyloid β protein (Aβ) subtypes. In four of five animals, all types of SPs (i.e. diffuse, primitive, and classical plaques; DPs, PPs, and CPs, respectively) were identified by BC05. However, BA27 did not label DPs and stained only about one third of PPs and CPs, mainly labeling granular structures and cored portions, respectively. In CAA, lesions of cortical capillaries reacted to BC05 in four of five cases, but rarely and weakly to BA27 in two of five cases. On the other hand, lesions of parenchymal and meningeal arterioles were stained by both BA27 and BC05. These staining profiles of SPs in cynomolgus monkeys correspond well to those in humans, although there are two remarkable features in cynomolgus monkeys. First, BA27 stained PPs associated with granular structures. Secondly, capillary Aβ reacted intensely to BC05 but only slightly to BA27. Despite these unique features, the results suggest that aged cynomolgus monkeys can be used to investigate the pathogenesis of Aβ deposition in SPs and CAA.
    Neuroscience Letters 01/1996; · 2.03 Impact Factor
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    ABSTRACT: The incidence and morphological characteristics of senile plaque and amyloid angiopathy in the cerebrum of six aged cynomolgus monkeys (Macaca fascicularis), 20 to 29 years old, were studied histopathologically and immunohistochemically. By periodic acid methenamine silver stain (PAM) and alkaline Congo red stain, senile plaques were detected in 5 out of 6 cases, and 3 of them were positive for amyloid in the wall of capillaries and arterioles in the cerebral cortex. Senile plaques were classified into three types. Mature plaques, including classical and primitive types, were more frequently observed than the immature diffuse type. Senile plaques were often seen in the cortex of temporal lobe, putamen and head of caudate nucleus. Since mature types of senile plaques were seen frequently around vascular amyloid deposition and no amyloid angiopathy was detected in the areas without senile plaques, the close relation between senile plaque of the mature type and amyloid angiopathy might be considered. All senile plaques and amyloid angiopathy were positively stained immunohistochemically with antibody against amyloid beta-protein (A beta P) 1-40 synthetic peptide, but all diffuse and some primitive plaques were negative for antibody against A beta P 8-17 synthetic peptide. Neither senile plaque nor amyloid angiopathy was detected in the cerebrum of 15 young monkeys, 9 to 11 years old, examined as controls.
    Experimental Animals 11/1995; 43(5):711-8. · 1.46 Impact Factor
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    ABSTRACT: Pneumocystis carinii (Pc) infection was observed in three of five rhesus monkeys infected with simian immunodeficiency virus (SIVmac251). They showed severe symptoms similar to those associated with human acquired immunodeficiency syndrome (AIDS). Histopathology revealed severe pulmonary pneumocystosis in one of three Pc-positive monkeys, and anti-Pc antibodies were detected in sera from two of the three monkeys. Localization of Pc organisms in various organs of the monkeys was examined by the polymerase-chain-reaction (PCR) method, and Pc-specific bands of DNA amplification were detected in the liver, kidney, spleen, adrenal gland, testis, brain, and other organs examined, but no Pc organism was found in these organs by histopathologic examination. These results suggest that the activation of a latent infection of Pc occurs in SIV-infected rhesus monkeys as well as in human AIDS. Experimental transmission of Pc derived from a simian was attempted in severe combined immunodeficiency (SCID) mice and athymic nude (rnu/rnu, F344) rats. These animals were inoculated intranasally with 10(4) Pc cysts, but neither histopathologic changes nor Pc organisms were detected in SCID mice at 4 months after inoculation or in nude rats at 2 months postinoculation, suggesting that simian Pc is species-specific.
    Parasitology Research 02/1993; 79(8):624-8. · 2.85 Impact Factor
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    ABSTRACT: An infection occurred in all African green monkeys and cynomolgus monkeys experimentally inoculated with SIVAGM [TYO-1], as demonstrated by the appearance of an antibody to SIVAGM [TYO-1] and the isolation of the virus. No monkey exhibited overt clinical disorders throughout the experimental period of 42 weeks. Thus, SIVAGM was not pathogenic to its original host or to macaques. This system is proposed as a model for HIV infection manifesting no overt disease.
    Journal of Medical Primatology 02/1990; 19(1):9-20. · 1.11 Impact Factor
  • I Sakakibara, S Honjo
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    ABSTRACT: Congenital polycystic kidney disease was diagnosed at necropsy in a stillborn male cynomolgus monkey (Macaca fascicularis). This case was very similar to infantile polycystic kidney disease in man and the rhesus monkey, except that no increase in number of intrahepatic bile ducts was observed.
    Journal of Medical Primatology 02/1990; 19(5):501-6. · 1.11 Impact Factor
  • M Takasaka, A Kohno, I Sakakibara, H Narita, S Honjo
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    ABSTRACT: Serious salmonellosis occurred in groups of cynomolgus monkeys newly imported into Tsukuba Primate Center for Medical Science from the Philippines in 1985. During the quarantine period, Salmonella typhimurium (29 strains) and S. stanley (1 strain) were isolated from 30 of 130 imported monkeys. Twenty-eight of the 30 infected monkeys excreted mainly watery diarrhea, and occasionally bloody mucous stool. Seven of the 28 clinical cases infected with S. typhimurium resulted in death or in moribund state. In both the small and large intestines of autopsied monkeys, acute inflammatory changes were observed.
    Japanese journal of medical science & biology 03/1988; 41(1):1-13.
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    ABSTRACT: Proviral integration of a simian retrovirus highly homologous to human T-cell leukemia virus type I was examined in cellular DNAs extracted from primary peripheral blood lymphocytes of 31 adult African green monkeys (Cercopithecus aethiops) that were seropositive for simian T-cell leukemia virus type I (STLV-I). Among these monkeys, one case with overt leukemia, showing pleomorphic leukemia cells similar to those in human adult T-cell leukemia (ATL), and five cases in a preleukemic state of ATL-like disease were found. Judging from the integration site of the provirus genome, primary lymphocytes of these leukemic or preleukemic cases contained monoclonally proliferated STLV-I-infected cells, whereas lymphocytes of other seropositive monkeys without hematological abnormalities were polyclonal, and those of seronegative monkeys did not contain the provirus. The restriction patterns with PstI ans SstI of most STLV-I proviruses were identical to those of the previous isolate from this species, but in three monkeys there was a deletion of one PstI site. From the correlation of the development of simian ATL-like disease with the monoclonal integration of the STLV-I provirus genome, it should be indicated that STLV-I has similar leukemogenicity to human T-cell leukemia virus type I, and so STLV-I infection in African green monkeys will be useful as an animal model of human ATL.
    Cancer Research 02/1987; 47(1):269-74. · 8.65 Impact Factor
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    ABSTRACT: An African green monkey naturally infected with simian T-lymphotropic virus (STLV) developed spontaneous malignant lymphoma of diffuse pleomorphic type. The clinical, hematological and histopathological characteristics were very similar to those of human adult T-cell leukemia.
    Journal of Medical Primatology 02/1986; 15(5):311-8. · 1.11 Impact Factor

Publication Stats

237 Citations
41.56 Total Impact Points

Institutions

  • 1993–2005
    • The University of Tokyo
      • • Faculty and Graduate School of Agriculture and Life Sceince
      • • Institute of Medical Science
      Tokyo, Tokyo-to, Japan
    • National Institute of Health Sciences, Japan
      Edo, Tōkyō, Japan
  • 1998–2004
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2000
    • Nippon Veterinary and Animal Science University
      • Department of Veterinary Pathology
      Edo, Tōkyō, Japan
  • 1990
    • National Eye Institute
      Maryland, United States