|Toru Iwaki||Last modified date：2021.06.23|
Professor / Pathobiology / Department of Basic Medicine / Faculty of Medical Sciences
|Toru Iwaki||Last modified date：2021.06.23|
|1.||Masahiro Shijo, Kaoru Yagita, Hideko Noguchi, Sachiko Koyama, Hideomi Hamasaki, Hiroyuki Honda, Takafumi Shimogawa, Ataru Nishimura, Koichi Arimura, Masahiro Mizoguchi, Takanari Kitazono, Toru Iwaki, Histopathological analysis of T-cell infiltration and chemokine at the human brain infarcts, 第62回日本神経病理学会総会学術研究会, 2021.05, 【Background】Immune response of T cells in ischemic brain infarcts has been focused on, and the new insights such as the behavior of regulatory T cells (Treg) and its chemotaxis are gained by rodent models. However, less have been described about this behavior in human.
【Method】Using immunohistochemistry, we analyzed the distribution of T cells (CD3+) including Treg (FoxP3+) and expression pattern of T cell-chemokines and its receptors in human 14 autopsied samples and 22 surgical samples of variating ischemic changes.
【Results】In the coagulation necrosis, mild infiltration of CD3+ cells, CCR7+ cells and expression of CCL19 in astrocytes were noted in peri-infarct area without any FoxP3+ cells. Infiltration of CD3+ cells was evident in the liquefactive necrosis, and peri-infarct area of liquefactive necrosis and cystic lesions. FoxP3+ cells were focally noted near the boundary of necrosis. Strong CCL19-expression was observed in the reactive astrocytes of peri-infarct regions and foamy macrophages of infarcted area. In the specimens with the placement of subacute electrodes, dense infiltration of FoxP3+ cells was noted in and around the lesions without evident CCL19-expression in astrocytes.
【Conclusion】The chemotaxis behavior of T cells could alter between times and regions of human brain infarct, and those of Treg in the boundary of necrosis might differ from other T cells..
|2.||吉富小都, 本田裕之, 濱﨑英臣, 岩城徹, ALS6のFUS陽性封入体におけるリン酸化TDP-43の蓄積, 第43回日本分子生物学会年会, 2020.12, It is known that mutations in fused in sarcoma (FUS) causes familial ALS (ALS6). FUS is one of the hnRNPs that plays a role in mRNA metabolism, microRNA biogenesis, and DNA-related functions. In ALS6, FUS inclusions are widely observed in the central nervous system. On the other hand, in sporadic ALS (SALS), TDP-43 inclusions, which is also one of hnRNPs, are the pathological hallmark. Recently, it revealed that TDP-43 inclusions of SALS contain FUS inclusions. In this study, we investigated immunohistochemically the association between FUS and TDP-43 in ALS6. We mainly examined the hippocampus and spinal cord of two autopsy cases with different FUS gene mutations (H517P and R521C). The former patient is 44 years old and the latter is 45 years old. A majority of FUS inclusions are found in granule cell layer and pyramidal cell layer of hippocampus. In the spinal cord, the loss of neurons was severe and only a few FUS-positive inclusions were detected. Immunohistochemistry for phosphorylated TDP-43 also revealed TDP-43 inclusions in granule cells and pyramidal cells. Double immunofluorescence for FUS and phosphorylated TDP-43 showed co-localization of neuronal inclusions. Out of the FUS inclusions, 63% has TDP43 inclusions in granule cells, 70.3% does in pyramidal cells. These percentages are high and the results were similar in both cases. Also, the mutated region is nuclear localization signal site in both cases. These cases were the first to show that accumulation of TDP-43 in FUS inclusions of ALS6. Different hnRNPs also tend to aggregate with each other, and it was speculated that they cause dysfunction not only in SALS but also in ALS6..|
|3.||中村文香, 濱崎英臣, 本田裕之, 岩城徹, 一般住民における心筋basophilic degenerationのアミロイドβタンパク蓄積とアルツハイマー病脳病理との比較研究, 第43回日本分子生物学会年会, 2020.12, Basophilic degeneration (BD) is one of the common intracellular inclusions in cardiomyocytes of the aging heart. BD is a distinct type of cardiomyopathies, which was not known to associate with specific diseases. Recent studies have revealed brain-heart axis, but little is known about the association between BD and brain pathology. BD includes amyloid (A) which is one of the pathological hallmarks of Alzheimer’s disease (AD), and then, we studied the relationship between AD pathologies and the deposition of BD in the general population. We analyzed 105 subjects autopsied in the Hisayama Study (52 to 103 years of age). We performed immunohistochemistry of heart tissues using A antibody. Eventually all BD were immunolabeled by A antibody. Then, we counted the number of BD and calculated whole area of the specimens to evaluate the positive ratio of BD in each specimen. The frequency of BD-lesions tended to increase with age. BD was observed from 60 years old. There were more cases with many BD-lesions between 75 and 90 years old. Although there was no significant difference between men and women, women tended to have larger number of BD than men (p=0.0626). Neuropathologically, we revealed that A pathologies were independent of BD. In each group, no significant changes were observed between BD and the CERAD neuritic plaque score, Thal phase showing the distribution of A. There was also no significance between BD and Braak and Braak stage of neurofibrillary tangles (NFTs), but the frequency of BD tended to increase with Braak stage. In conclusion, the number of BD increased with aging and there were no significant changes between BD and the degree of AD pathologies..|
|4.||Nona Abolhassani, Masaaki Hokama, Daisuke Saitou, Masahiro Shijo, Takashi Saito, Takaomi C. Saido, Mikita Suyama, Toru Iwaki, Yutaka Kiyohara, Yusaku Nakabeppu, Disturbed glutamate signaling in AD hippocampus revealed by an integrated analysis of altered expression profiles of genes in both human and mouse brains with Alzheimer’s disease pathology, 第42回日本分子生物学会, 2019.12, To identify molecular pathological alterations in Alzheimer’s disease (AD) brains, we had previously performed comparative gene expression profiling with human gene array using RNAs prepared from postmortem human brains donated for the Hisayama study. The hippocampi from AD brains showed the most significant alteration in gene expression profile. In the present study, in order to obtain a comprehensive view of gene expression profiles in AD hippocampus, we applied human transcriptome array and deep RNA-sequencing to the same samples. By integrative analysis of all 3 methods, we discovered top 494 significantly altered genes in human AD hippocampus. IPA analysis of the top genes revealed that neurotransmission and synaptic transmission are the top downregulated functions in human AD hippocampus. In hippocampi of 6 month-old AppNL-G-F/NL-G-F knock-in AD model mice which exhibit significant amyloidosis but not neuronal degeneration, we found that expression of Gfap and Cd68 genes are significantly upregulated together with genes categorized in the immune response of cells. Comparing the human and mouse data, we found 5 genes (SLC17A6, GFRA2, CACNB4, SHISA9, CNTN5), which were significantly downregulated in both human and mouse AD brains compared to non-AD groups. Most of these genes are related to presynaptic axonal transmission in glutamatergic neurons of hippocampus, suggesting that amyloid- accumulation affects glutamate transmission..|
|5.||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..|
|6.||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
|7.||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..
|8.||Masashi Watanabe, Soichi Kondo, Shiro Ohue, Katsumi Kito, Toru Iwaki, Kensho Okamoto, Immunophenotype of lymphocytic primary angiitis of the central nervous system: a case study, The 19th International Congress of Neuropathology, 2018.09, Introduction: The reports on immunohistochemical profiles about primary angiitis of the central nervous system (PACNS) are scant. Here we report a lymphocytic PACNS case.
Clinical summary: A 31-years-old man without past medical history fell down suddenly and showed generalized seizure for a few minutes. Neurological examinations showed only
amnesic aphasia. Brain MRI revealed multiple cortical and subcortical high intensity lesions in the left temporal and occipital lobes on FLAIR and T2-weighted images, many of which presented with small ring-enhancement. Cerebral angiography showed no significant regional stenosis. Blood investigations showed no findings with suspected neither inflammatory, infectious, nor collagen diseases. Cerebrospinal fluid analysis indicated mild increased protein concentrations with elevation of IL-6, anti-glutamate receptor antibodies, and granzyme B. Brain biopsy revealed lymphocytic vasculitis compatible with PACNS. Treatment with prednisolone and cyclophosphamide resolved both his clinical features and abnormal MRI findings.
Pathological findings: Hematoxylin and eosin staining showed marked infiltration of lymphocytes without evidence of atypia and monoclonality, presenting with stenosis of
arterioles in the cerebral parenchyma and meninges. Immunohistochemistry for lymphocytic markers revealed that CD3-positive T cells, which mainly consist of CD8-positive T cells, and CD20-positive B cells obviously infiltrated in the vessel wall and perivascular space, but randomly in the cerebral parenchyma. CD138-positive cells were not detected anywhere.
Conclusion: Although the number of literatures showing the immunophenotypes of PACNS are limited, a mixed population of CD8-positive T cells and CD20-positive B cells in the
affected vessels and brain tissue may be one of the common characteristics of lymphocytic PACNS..
|9.||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..
|10.||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..
|11.||鈴木 諭, 北川玲華, 岩城 徹, Anti-tumor effects of metformin against malignant glioma, 第36回日本脳腫瘍病理学会, 2018.09.|
|12.||Reiji Hommyo, Satoshi O Suzuki, ABOLHASSANI NONA, Hideomi Hamasaki, Masahiro Shijo, Norihisa Maeda, Hiroyuki Honda, Yusaku Nakabeppu, Toru Iwaki, ラット脳発生およびヒト筋萎縮性側索硬化症におけるCRYMの発現変化 Developmental profiles of CRYM in rat newborn brains and its decreased expression in pyramidal tract degeneration of amyotrophic lateral sclerosis, 第40回日本分子生物学会年会, 2017.12, 久山町研究の剖検脳を用いた網羅的発現解析により、Alzheimer病(AD)の海馬においてmu-crystallin (CRYM)のmRNAの発現が著明に減少することが見出された。我々はこれまで正常脳におけるCRYMの海馬錐体細胞、大脳皮質深層の錐体細胞および錐体路での発現と、ADの海馬錐体細胞におけるCRYMの発現低下を報告したが、その他の神経変性疾患におけるCRYMの発現変化については知見に乏しい。また、CRYMは齧歯類の中枢神経系において上位運動ニューロンや錐体路にて生後急速に発現が亢進した後、終生発現が持続することが報告されているが、発生段階ごとの発現パターンの詳細は明らかにされていない。本研究では、1) 錐体路病変を生じる疾患として筋萎縮性側索硬化症(ALS)におけるCRYMの発現変化を検討すること、2) ラット脳における生後の日齢によるCRYMの発現変化を調べ、発生段階での役割と成体における発現パターンの成り立ちを解明することを目的とした。ALS 3例の剖検脳パラフィン切片を用いてCRYMの発現変化を免疫組織化学的に検討したところ、全例で脊髄レベルの錐体路でCRYMの発現が消失していた。また、生後0、3、6、9、14、21、28日齢のSDラット脳におけるCRYMの発現を免疫染色およびWestern blottingにより検討した結果、生後早期より大脳皮質、海馬、錐体路においてCRYMの発現を認めた。Western blottingでは生後3-6日の段階で脳におけるCRYMの発現がプラトーに達していた。CRYMは甲状腺ホルモン輸送担体として組織の成長および発達に関わっていると考えられている他、ケチミンリダクターゼとしての酵素活性により細胞のストレス耐性に関与している可能性が示されてきた。本研究の結果よりCRYMは生後早期の神経細胞の成熟から成体における神経細胞の機能維持に至るまで重要な役割を果たしていることが示唆された。また、錐体路変性の有用なマーカーとなることが示された。.|
|13.||Reiji Hommyo, Hideomi Hamasaki, Masahiro Shijo, ABOLHASSANI NONA, Yusaku Nakabeppu, Toru Iwaki, Cellular distribution of CRYM in human brains and its alterations in Alzheimer’s disease, 第38回日本分子生物学会, 2015.12, 【Purpose】 The Hisayama study using a series of autopsied brains revealed that mRNA of mu-crystallin (CRYM) was significantly decreased in the hippocampi of Alzheimer’s disease (AD) patients. In this study, we evaluated cellular distribution of CRYM in normal human brains and its alternation in AD hippocampi.
【Method】 We performed immunohistochemistry with two antibodies against CRYM. We examined autopsied brain samples from the Hisayama study.
【Results】 Immunoreactivity of CRYM was constantly observed in neurons of the cortical layer 3 and layer 5, caudate nucleus, putamen and hippocampus. In the cerebellum, diffuse neuropil staining was observed in the molecular layer. In AD, CRYM-immunopositive cells in the hippocampi were reduced to various degrees. The loss of CRYM was often observed in the hippocampal neurons with formation of pretangles.
【Conclusion】 Since CRYM is expressed mainly in the neurons of the brain areas vulnerable to ischemia and its function is regulated in the presence of NADPH, CRYM in neurons may be related to oxidative stresses. In AD hippocampi, CRYM expression was reduced in hippocampal neurons, particularly in the pretangle-bearing neurons..
|14.||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..|
|15.||ABOLHASSANI NONA, Masaaki Hokama, 齋藤 大助, Mikita Suyama, 岩城 徹, 清原 裕, 中別府 雄作, Characterization of transcript variants expressed in Alzheimer’s disease brains with human transcriptome array and deep RNA sequencing analyses: The Hisayama Study, 第38回日本神経科学大会, 2015.07.|
|16.||岡 素雅子, Julio Leon, ABOLHASSANI NONA, Masaaki Hokama, Toru Iwaki, Yutaka Kiyohara, Dongchon Kang, Yusaku Nakabeppu, Interspecies comparative gene expression profiling revealed impaired insulin production and insulin signaling in Alzheimer's disease brains: The Hisayama Study, The 2015 Alzheimer's DIsease Congress, 2015.06, To identify molecular pathological alterations in Alzheimer’s disease (AD) brains, we performed interspecies comparative microarray analyses using RNA prepared from postmortem human brain tissues donated for the Hisayama study, and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD). We found altered expression of genes involved in insulin production, insulin signaling and mitochondrial function in AD brains. Mitochondrial dysfunction is considered to have a pivotal role for developing AD, we further examined effects of human mitochondrial transcriptional factor A (hTFAM) transgene, which plays important roles to maintain mitochondrial homeostasis, on the pathology of 3xTg-AD mice..|
|17.||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..|
|18.||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..|