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Toru Iwaki Last modified date：2020.12.24

Professor / Pathobiology
Department of Basic Medicine
Faculty of Medical Sciences


Graduate School
Department of Integrative Biomedical Sciences
Graduate School of Medical Sciences
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Department of Medicine
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Homepage
https://kyushu-u.pure.elsevier.com/en/persons/toru-iwaki
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http://www.med.kyushu-u.ac.jp/neuropath/
Web site of Department of Neuropathology .
Phone
092-642-5536
Fax
092-642-5540
Academic Degree
Medical doctor
Country of degree conferring institution (Overseas)
No
Field of Specialization
Medicine, Pathology, Neuropathology, Neuroscience
Total Priod of education and research career in the foreign country
02years07months
Outline Activities
Subject of studies
(1) Clinicopathological study on dementia: the Hisayama study
The Hisayama study is a prospective population-based study in a Japanese subrural community, Hisayama Town, which has been carried out by Department of Medicine and Clinical Science, Kyushu University since 1961. The characteristic of the town is that the age, occupational status and nutrient intake of the population are almost identical to those of the general Japanese population. Postmortem examinations of most deceased subjects were performed in Kyushu University Hospital to confirm causes of death and to examine brain pathology. These features have allowed a reliable estimation of the frequency of neurodegenerative diseases relating dementia in a general population and for a detailed analysis of the difference between dementia and non-dementia. Our database based on the Hisayama study would have benefits to examine clinicopathological features of neurodegenerative diseases in a general population.
The prevalence of diabetes is growing at epidemic proportions worldwide, and is becoming a major health problem. Several large longitudinal population-based studies have shown that the rate of cognitive decline is accelerated in elderly people with type 2 diabetes compared with the general population. Similarly, other epidemiologic studies have revealed that diabetes increases the risk of dementia, including Alzheimer disease. Therefore, the effect of diabetes on cognitive function in the elderly has significant public health implications. We examined the association between diabetes-related factors and pathology of Alzheimer disease to evaluate how diabetes affects the pathogenic process of Alzheimer disease. The associations between each diabetes-related factor and Alzheimer disease pathology were examined by analysis of covariance and logistic regression analyses. The results suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate neuritic plague formation in combination with the effects of APOE epsilon4.

(2) Prion diseases
Prion diseases are a group of fatal neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD) in humans. We have performed clinicopathological studies on human prion diseases in a planned and consistent way. Prion diseases are associated with abnormal deposition of prion protein (PrP). The normal, cellular PrP (PrPc) is converted into abnormal PrP (PrPsc) through a process of conformational change where a portion of its alpha-helical and coil structure is refolded into a beta-sheet. Prion diseases are conventionally diagnosed by the detection of accumulation of abnormal PrP using immunohistochemistry or the detection of the abnormal PrP with protease resistance (PrPres). It would be highly recommended that the abnormality of PrP molecules should be determined from various perspectives more than protease resistance. We tested several spin columns to detect PrP oligomers by a simplified method applying gel filtration chromatography without protease treatment, in CJD patients with various degree of neuropathological change, and evaluated the correlation between the disease severity and the degree of PrP polymerization.

Education
(1) Undergraduate education
In the undergraduate teaching curriculum, a further investigation of the education for the diseases of the nervous system was established. To give the outline of the clinical neuroscience and neuropathology to the 3rd year students, I am in charge of the classes of clinical pathology and neuropathology.
(2) Postgraduate education
a. Neuropathology training
b. Clinico-pathological conference
Research
Research Interests
  • Identification of risk factors for the pathological changes of the demented brains through morphometric assessments
    keyword : Alzheimer's disease, dementia, tauopathy
    2014.04～2019.03Clinicopathological study on dementia (the Hisayama study).
  • Pathological study on glioma
    keyword : brain, glioma, metabolism, pathology
    2012.04～2018.03Cell biological study on glioma stem cell.
  • Clinicopathological study on dementia (the Hisayama study)
    keyword : Alzheimer's disease, dementia
    2002.04～2014.03Clinicopathological study on dementia (the Hisayama study).
  • Cell biological study on glioma stem cell
    keyword : glioma, cancer stem cell, tumorigenesis
    2005.04～2007.03Cell biological study on glioma stem cell .
  • Clinicopathological study on prion disease
    keyword : Prion, Creutzfeldt-Jakob disease
    1989.11Clinicopathological study on prion diseases Development of diagnostic tool for prion diseases.
  • Developmental study of the central nervous system
    keyword : central nervous system, development, glia
    2003.01～2011.03Developmental study of the central nervous system.
  • Study on stress proteins in neurological diseases
    keyword : stress protein, alphaB-crystallin, heat shock protein
    1997.05～2006.03Study on stress proteins in neurological diseases.
Current and Past Project
  • The Kyushu University COE Program on Lifestyle-Related Diseases
Academic Activities
Books
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Papers
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1. Shoko Sadashima, Hiroyuki Honda, Satoshi O. Suzuki, Masahiro Shijo, Shinichi Aishima, Keita Kai, Junichi Kira, Toru Iwaki, Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques, J Neuropathol Exp Neurol, 10.1093/jnen/nlaa010, 79, 4, 419-429, 2020.04, Gerstmann-Str€aussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases..
2. Shinichiro Mori, Hiroyuki Honda, Takashi Ishii, Motoi Yoshimura, Naokazu Sasagasako, Satoshi O. Suzuki, Takayuki Taniwaki, Toru Iwaki, Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)-binding protein 1 in Huntington's disease, Neuropathology, 10.1111/neup.12600, 39, 5, 358-367, 2019.10, Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis..
3. Hiroyuki Honda, Masaki Matsumoto, Masahiro Shijo, Hideomi Hamasaki, Shoko Sadashima, Satoshi O. Suzuki, Shinichi Aishima, Keita Kai, Keiichi I. Nakayama, Naokazu Sasagasako, Toru Iwaki, Frequent Detection of Pituitary-Derived PrPres in Human Prion Diseases, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlz075, 78, 10, 922-929, 2019.10, Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells..
4. Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Koji Iihara, Toru Iwaki, Upregulation of Annexin A1 in Reactive Astrocytes and Its Subtle Induction in Microglia at the Boundaries of Human Brain Infarcts, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlz079, 78, 10, 961-970, 2019.10, Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage..
5. Shijo M, Honda H, Suzuki SO, Hamasaki H, Hokama M, Abolhassani N, Nakabeppu Y, Ninomiya T, Kitazono T, Iwaki T., Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi, Brain Pathol., 10.1111/bpa.12475, 28, 1, 58-71, 2019.01, Adipocyte enhancer binding protein 1 (AEBP1) activates inflammatory responses via the NF-κB pathway in macrophages and regulates adipogenesis in preadipocytes. Up-regulation of AEBP1 in the hippocampi of patients with Alzheimer's disease (AD) has been revealed by microarray analyses of autopsied brains from the Japanese general population (the Hisayama study). In this study, we compared the expression patterns of AEBP1 in normal and AD brains, including in the hippocampus, using immunohistochemistry. The subjects were 24 AD cases and 52 non-AD cases. Brain specimens were immunostained with antibodies against AEBP1, tau protein, amyloid β protein, NF-κB, GFAP and Iba-1. In normal brains, AEBP1 immunoreactivity mainly localized to the perikarya of hippocampal pyramidal neurons, and its expression was elevated in the pyramidal neurons and some astrocytes in AD hippocampi. Although AEBP1 immunoreactivity was almost absent in neurons containing neurofibrillary tangles, AEBP1 was highly expressed in neurons with pretangles and in the tau-immunopositive, dystrophic neurites of senile plaques. Nuclear localization of NF-κB was also observed in certain AEBP1-positive neurons in AD cases. Comparison of AD and non-AD cases suggested a positive correlation between the expression level of AEBP1 and the degree of amyloid β pathology. These findings imply that AEBP1 protein has a role in the progression of AD pathology..
6. Norihisa Maeda, Hiroyuki Honda, Satoshi Suzuki, Naoki Fujii, Jun-Ichi Kira, Toru Iwaki, Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy, Neuropathology, 10.1111/neup.12482, 38, 4, 361-371, 2018.08, Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA..
7. Chang Shen, Hiroyuki Honda, Satoshi Suzuki, Norihisa Maeda, Masahiro Shijo, Hideomi Hamasaki, Naokazu Sasagasako, Naoki Fujii, Toru Iwaki, Dynactin is involved in Lewy body pathology, Neuropathology, 10.1111/neup.12512, 2018.02, Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology..
8. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T, Insulin resistance is associated with the pathology of Alzheimer’s disease: the Hisayama Study., Neurology, 10.1212/WNL.0b013e3181eee25f, 75, 9, 764-770, Epub 2010 Aug 25., 2010.08, タイトル：インスリン抵抗性はアルツハイマー病の脳病理と関連する
目的：我々は、糖尿病がAlzheimer病（AD）の病理学的過程にどのように影響を与えるのかについて評価するために、糖尿病関連因子とAD病理との関連について検討を行った。
方法：この研究では、福岡県久山町の住民のうち、1998年から2003年までに死亡し、かつ1988年の検診にて75g経口血糖負荷試験を施行された連続剖検135名（男性74名、女性61名）の検体を用いた。我々は、1988年の検診において、糖尿病関連因子として、空腹時血糖、糖負荷2時間後血糖、空腹時インスリン、インスリン抵抗性評価尺度（HOMA-IR）を測定した。脳内の老人斑についてはCERADガイドライン、神経原線維変化についてはBraakステージ分類に基づいて評価した。各因子とAD病理との関連についての解析は、共分散分析とロジスティック解析を行った。
結果：解析にて、性、年齢、収縮期血圧、総コレステロール、BMI、喫煙、運動、脳血管障害で調整すると、糖負荷2時間後血糖、空腹時インスリン、HOMA-IRの高値が、老人斑のリスクの上昇と関連した。しかし、糖尿病関連因子と神経原線維変化については、有意な関連を認めなかった。AD病理のリスクに関して、アポリポ蛋白E（APOE）の遺伝子型を考慮すると、高血糖とAPOEε4が共存すると、老人斑形成のリスクが上がった。同様の傾向は、高インスリン血症やHOMA-IR高値でも認められた。
結論：この研究から、インスリン抵抗性によって引き起こされる高インスリン血症、高血糖が、APOEε4とともに、老人斑形成を加速させることが示唆された。
Objective: We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD.
Methods: This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses.
Results: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon 4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.
Conclusion: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon 4..
9. Fujii N, Furuta A, Yamaguchi H, Nakanishi K, Iwaki T., Limbic encephalitis associated with recurrent thymoma: A postmortem study, Neurology, 57, 2, 344-347, 57:344-347, 2001.01.
10. Suzuki SO, Mizoguchi M, Iwaki T, Detection of SV40 T antigen genome in human gliomas., Brain Tumor Pathol., 14: 125-129, 1997.01.
11. Suzuki SO, Iwaki T, Kitamoto T, Fukui M, Tateishi J, Differential expression of CD44 variants among meningioma subtypes., J. Clin. Pathol: Clin. Mol. Pathol., 49, 3, M140-M146, 49: M140-M146, 1996., 1996.01.
12. Hitotsumatsu T, Iwaki T, Fukui, M, Tateishi J, Distinctive immunohistochemical profiles of small heat shock proteins (heat shock protein 27 and alphaB-crystallin) in human brain tumors., Cancer, 10.1002/(SICI)1097-0142(19960115)77:2<352::AID-CNCR19>3.0.CO;2-0, 77, 2, 352-361, 77: 352-361, 1996.01.
13. Masaru Ohta, Tom Iwaki, Tetsuyuki Kitamoto, Iwao Takeshita, Jun Tateishi, Masashi Fukui, MIB1 staining index and scoring of histologic features in meningioma. Indicators for the prediction of biologic potential and postoperative management, Cancer, 10.1002/1097-0142(19941215)74:12<3176::aid-cncr2820741217>3.0.co;2-n, 74, 12, 3176-3189, 74: 3176-3189, 1994.12.
14. Iwaki T, Wisniewski T, Iwaki A, Corbin E, Tomokane N, Tateishi J, Goldman JE:, Accumulation of alphaB-crystallin in central nervous system glia and neurons in pathologic conditions., Am. J. Pathol., 140, 2, 345-356, 1992.02.
15. Iwaki T, Kume-Iwaki A, Liem RKH, Goldman JE, alphaB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain., Cell, 10.1016/0092-8674(89)90173-6, 57, 1, 71-78, 1989.04, Rosenthal fibers (RFs) are abnormal inclusions within astrocytes, characteristic of Alexander's disease. We have previously isolated a 22 kd protein component of RFs from Alexander's disease brain. By Western blotting, we detected its equivalent in several rat organs, with the highest level in heart, and in a human astrocytoma cell line (U-373MG). A cDNA library established from U-373MG was screened with an anti-RF protein antibody. A partial cDNA clone encoding the lens protein alpha B-crystallin was isolated. The anti-RF protein antibodies react with lens alpha B-crystallin. Furthermore, the distribution of alpha B-crystallin mRNA in rat organs is consistent with the Western blots. Therefore, alpha B-crystallin is not lens-specific and it can accumulate in large amounts in astrocytes in pathological conditions..
Presentations
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1. Hiroyuki Honda, Chang Shen, Satoshi O Suzuki, Naokazu Sasagasako, Toru Iwaki, Dynactin is involved in Lewy body pathology, The 19th International Congress of Neuropathology, 2018.09, Introduction: Dynactin forms a protein complex with dynein and the complex transports cargo retrogradely along microtubules. Dysfunction of the dynein-dynactin complex causes several neurodegenerative disorders, such as Perry syndrome. Recently, we reported colocalization of phosphorylated alpha-synuclein (p-SCNA) and the largest subunit of dynactin (DCTN1) in Lewy body-like structures in Perry syndrome. However, the relationship between dynactin and synucleinopathies has not been clarified. In this study, we examined the possible involvement of the dynein-dynactin complex in synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Methods: We examined 13 autopsied human brains of patients with synucleinopathy (5 PD, 5 DLB and 3 MSA). Immunohistochemistry for p-SNCA, DCTN1 (dynactin) and DYNC1I1 (dynein) was performed. We also examined microtubule affinity regulating kinases (p-MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Double immunofluorescence was also performed. Results: Both brainstem and cortical Lewy bodies were immunopositive for DCTN1, DYNC1I1 and p-MARK and their stainings often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1 and DYNC1I1. However, p-SNCA-positive inclusions of MSA such as glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were negative for DCTN1, DYNC1I1 and p-MARK. Conclusion: Our results suggest that dynactin is closely associated with Lewy body pathology. In addition, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can distinguish Lewy bodies clearly from neuronal cytoplasmic inclusions of MSA..
2. Reiji Hommyo, Satoshi O Suzuki, Nona Abolhassani, Hideomi Hamasaki, Masahiro Shijo, Norihisa Maeda, Hiroyuki Honda, Yusaku Nakabeppu, Toru Iwaki, Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis, The 19th International Congress of Neuropathology, 2018.09, Introduction: Down-regulation of μ-crystallin (CRYM) in the hippocampi of patients with Alzheimer's disease was revealed by microarray analyses of autopsied brains from the
Japanese general population (the Hisayama study). CRYM reportedly has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. We examined the expression pattern of CRYM in the rat brain during development. As CRYM is reportedly expressed in the corticospinal tract (CST), we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS).
Methods: CRYM expression in developing rat brains was examined by immunohistochemistry and immunoblotting. CRYM expression in human ALS brains was examined by immunohistochemistry. Results: In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and CST in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. In these regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In human ALS brains, we observed marked loss of CRYM in the CST, especially distally.
Conclusion: CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and later performs cell-specific functions in selected neuronal populations. The expression patterns of CRYM may reflect interactions with T3 or ketimines. The results also indicate that CRYM can be used as a marker of axonal degeneration in the
CST..
3. Shinichirou Mori, Akihiro Watanabe, Masahiro Shijo, Hiroyuki Honda, Satoshi O Suzuki, Naokazu Sasagasako, Toru Iwaki, An autopsy case of SPG11 with peculiar p62-immunopositive intracytoplasmic inclusions, The 19th International Congress of Neuropathology, 2018.09, Introduction: SPG11 is an autosomal recessive inherited spastic paraplegia with thin corpus callosum. Biallelic mutation in the SPG11 gene can also cause juvenile-onset amyotrophic lateral sclerosis-5 (ALS5) and Charcot-Marie-Tooth disease type 2X (CMT2X), different neurodegenerative disorders with overlapping features. Here, we report an autopsy case of SPG11 with IVS18+1G>T homozygous mutation.
Clinical summary: At 27 years of age, the patient developed lower limb spasticity, and the symptom gradually worsened. Her elderly brother also suffered to same symptom. By age 44 years, she was wheelchair-bound and severely demented. She died of esophageal perforation at the age of 57 years. A cardiac uptake of 123I-metaiodobenzylguanidine is reduced, suggesting the cardiac sympathetic denervation.Autopsy findings: The brain weighed 786g. Severe cerebral atrophy and thin corpus callosum were noted. Histologically, large intracytoplasmic eosinophilic granular structures with vacuoles were observed in spinal root ganglia. Many coarse eosinophilic granules are also noted throughout the CNS. These eosinophilic structures are highlighted by immunohistochemistry for p62, but negative for p-TDP43 and p-tau. Additionally, rather small p-TDP43 positive neuronal inclusions are observed in the brain and spinal cord, however, no skein-like inclusions were detected. Neuronal loss of substantia nigra was severe. Tyrosine hydroxylase-positive nerve fibers were markedly diminished at the pericardium.
Conclusion: The autopsy findings demonstrated that SPG11 involved widespread neuronal structures: cerebral cortex, corticospinal tracts, extrapyramidal nuclei, and peripheral nervous system including sympathetic nerves. Large eosinophilic bodies in the spinal ganglion cells with vacuoles may be most notable characteristic feature of SPG11. p-TDP43 depositions were also widely observed..
4. Masahiro Shijo, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Hiroyuki Honda, Satoshi O Suzuki, Toru Iwaki, Upregulation of annexin A1 in reactive astrocytes at the boundaries of human brain infarcts, The 19th International Congress of Neuropathology, 2018.09, Introduction: Annexin A1 (ANXA1) is mainly expressed in astrocytes and ependymal cells of normal human brains. Regarding acute ischemic brain, increased expression of ANXA1 in microglia and vascular endothelium has been shown with rodent models; however, astrocytic expression of ANXA1 in infarcted brain tissues has been little focused on.
Methods: We performed immunohistochemistry in autopsied human brain tissues from 15 cases with cerebral infarction, and the brain tissues of CB-17 mouse stroke model
generated by occlusion of the middle cerebral artery. Result: Marked expression of ANXA1 was noted in the viable regions adjacent to necrosis. ANXA1 was mainly distributed in
astrocytes rather than microglia at the viable boundary area, as well as in macrophages and endothelium at the necrotic area. Compared with the area of fibrillary gliosis revealed by GFAP, ANXA1-immunopositive area was restricted in the narrow band of viable periinfarct region. TMEM119-immunopositive resident microglia gathered in the periphery of necrosis, but this population was decreased in the ANXA1-immunopositive periinfarct areas. ANXA1 expression in microglia, macrophages and endothelium was also noted in the mouse ischemic brains, however, astrocytic ANXA1 was not observed regardless of the duration of ischemia.
Conclusion: ANXA1 expression was elevated in reactive astrocytes around necrosis during acute ischemia of human brains. Astrocytic ANXA1 could affect the behavior of resident
microglia through the strong anti-inflammatory properties. The act of ANXA1 during focal brain ischemia might be different between human and mouse species..
5. Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Satoshi O Suzuki, Toshiharu Ninomiya, Toru Iwaki, Putaminal Tau Pathology in the Aging Japanese Population: The Hisayama Study, The 19th International Congress of Neuropathology, 2018.09, Introduction: Hisayama study is a prospective cohort study commenced in 1961 in the town of Hisayama in Fukuoka Prefecture, Japan. In principle, all residents of the town of
Hisayama are proposed to be autopsied when they die, and the total autopsy rate is about 75%. We previously reported that Alzheimer's disease (AD) and hippocampal tau deposits were increasing in recent years in Japan. In this study, we extend our observation towards putaminal tau pathology in the aging Japanese population.
Methods: We examined a series of autopsied cases from Hisayama residents obtained between 2009 and 2014 (224 cases). To evaluate tau pathology quantitatively, we performed immunohistochemistry with AT8 antibody and automated quantitative analysis using a platform called MATLAB.
Results: Tau deposits in putamen gradually increased around 70 years of age, and were correlated with the Braak stage. Certain AD cases showed severe tau deposits in putamen. Amyloid deposition in the putamen was not necessarily correlated with the putaminal tau deposition. We subdivided all cases into low CERAD (CERAD score 0-1) and high CERAD (CERAD score 2-3) groups to examine the effect of cerebral amyloid deposits on the putaminal tau pathology. The areal mean of putaminal tau deposition was significantly higher in the high CERAD group.
Conclusion: The cases with severe tau deposits in putamen were largely attributed to AD in the aging population..
6. Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O Suzuki, Yusaku Nakabeppu, Toru Iwaki, Correlation between neuropathologic changes of Alzheimer’s disease and cellular distribution of AE-binding protein 1 (AEBP1) in human hippocampi, 第38回日本分子生物学会, 2015.12, Adipocyte enhancer binding protein 1 (AE-binding protein 1, AEBP1) has functions to activate inflammatory response via NF-κB pathway in macrophages and to regulate adipogenesis in preadipocytes. Whereas the function of AEBP1 in CNS is unknown, we have previously reported increased mRNA of AEBP1 in human hippocampi of Alzheimer’s disease (AD) patients. In this research we examined cellular distribution of AEBP1 protein in human hippocampi and correlation to neuropathologic changes of AD in autopsy cases of Hisayama residents. Immunohistochemistry revealed that AEBP1 was mainly localized in neuronal perikarya of human hippocampi, and expression of AEBP1 was elevated in pyramidal cells and some astrocytes of AD patients. Although AEBP1 was depleted in the neurons bearing neurofibrillary tangles, AEBP1 was highly expressed in the neurons with pretangles and in the dystrophic neurites of senile plaques. Nuclear localization of NF-κB was also observed in many AEBP1-positive neurons of AD patients. The comparison of AD cases and non AD cases showed there seemed to be positive correlation between AEBP1 expression and progression of β amyloid pathology. These findings may imply that AEBP1 protein has a role in progression of AD. On the other hand, constitutive expression of AEBP1 in neurons suggest that AEBP1 may also contribute to normal neuronal function..
7. Hideomi Hamasaki, HIROYUKI HONDA, Tomihiro Wakamiya, Satoshi O Suzuki, Toru Iwaki, Distribution of carnitine palmitoyltransferase(CPT) 1C in the subdivisions of human hippocampi and the alterations in Alzheimer’s disease brains., 第37回日本分子生物学会, 2014.11, The previous study has shown mRNA of carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform of the CPT1 family, downregulated in Alzheimer’s disease (AD) brain, which highlighted in hippocampus. 3 Therefore, we examined the cellular component-dependent changes of CPT1C expressions in human hippocampus. For immunohistochemistry we examined the medial temporal lobe including hippocampus using an anti-CPT1C antibody, which recognizes its internal region. The subjects were 17 AD cases and 21 normal controls without brain diseases. In normal brains, CPT1C immunoreactivity was mainly perikarya of the neurons. Some nuclei of neurons and glial cells are immunopositive for CPT1C. In AD brains, we found decline of CPT1C immunoreactivity in perikarya of the pyramidal cells dominantly in CA1 area. On the other hand, granulovacuolar degeneration was strongly immunopositive for CPT1C. Given CPT1C is concerned with memory function, the reduction of CPT1C in AD hippocampus indicates CPT1C is one of the cause of memory dysfunction in AD..
8. Hideomi Hamasaki, HIROYUKI HONDA, Satoshi O Suzuki, Toru Iwaki, Altered expression of c-Met in Alzheimer’s disease brains., 第35回日本分子生物学会, 2012.12, The Hisayama study using a series of autopsied brains revealed that messenger RNA of c-Met, the receptor of hepatocyte growth factor (HGF), was significantly decreased in the hippocampus of Alzheimer’s disease (AD) patients. Therefore, we examined the expression pattern of c-Met by immunohistochemistry. In normal controls, c-Met immunostaining was observed in the perikarya of pyramidal neurons of hippocampi and a subpopulation of astrocytes mainly at the subpial layer and perivascular regions. In AD brains, we found marked decline of perikaryal staining of hippocampal neurons. Additionally, we found the strong immunostaining of c-Met in reactive astrocytes including those in the vicinity of senile plaques. Since it has been reported that HGF was also up-regulated around the senile plaques, b-amyloid deposition may be associated with reactive astrocytosis through HGF signaling pathway. On the contrary, HGF signaling in the hippocampal neurons may be markedly reduced by depletion of c-Met. In the transgenic mouse model, overexpression of HGF in neurons resulted in enhanced memory function. Thus, the neuronal depletion of c-Met in AD brains may be associated with the cognitive impairment..
Membership in Academic Society
  • The Society for Neuroscience
  • The Molecular Biology Society of Japan
  • The Japanese Society of Neuropathology
  • The Japanese Society of Pathology
  • The Japan Society of Brain Tumor Pathology
  • The International Society of Neuropathology
  • Japanese Society of Neuropathology
  • Japanese Society of Pathology
  • Japan Society of Brain Tumor Pathology
  • International Society of Neuropathology
Educational
Educational Activities
1) Postgraduate education
Department of Neuropathology, Graduate School of Medical Sciences.
2) Undergraduate education
Medical history (2nd year), Medical School
Pathology (3rd year), Medical School
Neurological Course of Clinical Medicine (3rd year), Medical School
Chairman of Committee of Student Affairs, Medical School (2001)
Member of Committees of Student Affairs and Education, Medical School (2000-2011)
Other Educational Activities
  • 2010.04.
Social
Professional and Outreach Activities
The Japanese Society of Neuropathology (Board)
The International Society of Neuropathology（Councilor）
The Japan Society of Brain Tumor Pathology (Board)
The Japanese Society of Pathology（Councilor）
Neuropathology (Editor in Chief, 2012-2017)
Pathology International　（Editor）
Brain Tumor Pathology （Editor）.


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