2002 Fiscal Year Annual Research Report

神経変性疾患における終末糖化産物(AGE-2構造体)の細胞障害機構の解明

Research Project

Project/Area Number	13470197
Research Institution	Hokuriku University
Principal Investigator	竹内正義北陸大学, 薬学部, 講師 (20154982)
Co-Investigator(Kenkyū-buntansha)	佐々木信幸札幌医科大学, 医学部, 助手 (60315497) 菊地誠志北海道大学, 大学院・医学研究科, 講師 (10271660)
Keywords	終末糖化産物 / Advanced Glycation End-product / AGE-2構造体 / Aβ(1→40) / AGE-2化Aβ(1→40) / グリケーション / アルツハイマー病 / 神経変性疾患
Research Abstract	アルツハイマー病をはじめとする多くの神経変性疾患では、共通に異常タンパク質の産出、蓄積が観察され、その後共通の分子メカニズムによって神経細胞の変性と死が引き起こされると想定されている。申請者は、この病的な異常タンパク質の蓄積ならびに神経細胞の変性と死に終末糖化産物(AGE : Advanced Glycation End-products)が直接関与しているとする仮説に基づき、これまで研究を遂行して来ている。平成13年度補助金により、申請者が世界に先駆けて発見した新規終末糖化産物(AGE-2構造体)が、神経細胞培養系において直接的な細胞毒性(アポトーシスによるニューロン死)を示すのみならず、神経細胞等に栄養素を供給している血管内皮細胞にも直接作用して血栓形成や虚血傾向を示すことを明らかにした。平成14年度においては、AGE-2化Aβ(1→40)およびAβ(1→42)を作製し、ニューロン、アストロサイト、ミクログリアに対するAGE-2構造体の意義を検討した。その結果、ニューロンおよびミクログリアでは、AGE-2化の影響は観察されなかったが、アストロサイトにおいては、AGE-2化Aβが有意に毒性を示すことが明らかになった。さらに、AGE-2特異抗体を用いたAD脳の免疫染色の結果、ニューロンとアストロサイトにAGE-2構造体が局在していることが明らかとなった。恐らくAGE-2構造体は、ニューロンやアストロサイトの細胞膜レセプターを介した細胞外からの作用の他、これらの細胞内でAGE-2構造が形成され、細胞内の機能異常を介して、アルツハイマー病の原因に関与していることが推察されたが、今後さらなる詳細な検討が必要と考えられる。また、孤発性筋萎縮性側索硬化症(ALS)患者病変部およびクロイツフェルト・ヤコブ病患者プリオンプラークにもAGEの蓄積が観察されており、これらの神経変性疾患の病因としてもAGE形成反応が注目される。

Research Products

(29 results)

All Other

All Publications (29 results)

[Publications] 菊地誠志, 竹内正義, 佐々木信幸他4名: "Glycation-A sweet tempter for neuronal death-"Brain Res.Review. (印刷中). (2003)
[Publications] 竹内正義, 佐々木信幸, 菊地誠志他10名: "Neurotoxicity of acetaldehyde-derived advanced glycation end-products for cultured cortical neurons"J.Neuropathol.Exp.Neurol.. (印刷中). (2003)
[Publications] 山岸昌一, 竹内正義, 佐々木信幸, 菊地誠志他5名: "Angiotensin II-type 1 receptor interaction inhibits DNA synthesis and up-regulates vascular endothelial growth factor mRNA levels in retinal pericytes through intracellular reactive oxygen species generation"Drugs Exp.Clin.Res.. (印刷中). (2003)
[Publications] 山岸昌一, 竹内正義他3名: "Leptin stimulates proliferation of microvascular endothelial cells through autocrine vascular endothelial wth factor production-a possible participation of reactive oxygen species in leptin-induced angiogenesis-"Microvas.Res.. (印刷中). (2003)
[Publications] 三浦順之助, 竹内正義他11名: "AGE downregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J.Diabetes Complicat.. (印刷中). (2003)
[Publications] 米倉秀人, 竹内正義他11名: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, ad their putative roles in diabetes-induced vascular injury"Biochem.J.. (印刷中). (2003)
[Publications] 菊地誠志, 竹内正義他7名: "Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons"Brain Res.. 964. 228-236 (2003)
[Publications] 山岸昌一, 竹内正義他3名: "Leptin up-regulates vascular endothelial growth factor and down-regulates pigment epithelium-derived factor mRNA levels in cultured retinal pericytes"Int.J.Tissue React.. (印刷中). (2003)
[Publications] 稲垣洋介, 竹内正義他3名: "Pigment epithelium-derived factor prevents advanced glycation end products-induced monocyte chemoattractant protein-1 production in microvascular endothelial cells by suppressing intracellular reactive oxygen species generation"Diabetologia. 46. 284-287 (2003)
[Publications] 山岸昌一, 竹内正義他4名: "Advanced glycation end products inhibit de novo protein synthesis and induce TGF-β overexpression in proximal tubular cells"Kidney Int.. 63. 464-473 (2003)
[Publications] 山岸昌一, 竹内正義他4名: "Dilazep hydrochloride, an antiplatelet drug, prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Drugs Exp.Clin.Res.. (印刷中). (2003)
[Publications] 三浦順之助, 竹内正義他5名: "Serum leveles of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes"J.Diabetes Complicat.. 17. 16-21 (2003)
[Publications] 天野伸治郎, 竹内正義他9名: "Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes"Biochem.Biophys.Res.Commun.. 299. 183-188 (2002)
[Publications] 岡本珠美, 竹内正義他7名: "Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin"FASEB J.. 16. 1928-1930 (2002)
[Publications] Petrova R, 竹内正義他12名: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J.Mol.Cell.Cardiol.. 34. 1425-1431 (2002)
[Publications] 古賀康八郎, 竹内正義他7名: "CS-866, a New angiotensin II type 1 receptor antagonist, Ameliorates glomerular anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Mol.Med.. 8. 591-599 (2002)
[Publications] 菊地誠志, 竹内正義他5名: "Detection of N-(carboxymethyl)lysine (CML) and non-CML advanced glycation end products in the anterior horn of amyotrophic lateral sclerosis spinal cord"Amyotroph.Lateral Scler.Other Motor Neuron Disord.. 3. 63-68 (2002)
[Publications] 山岸昌一, 竹内正義他4名: "Beraprost sodium, a prostaglandin I_2 analogue, protects against advanced glycation end products-induced injury in cultured retinal pericytes"Mol.Med.. 8. 546-550 (2002)
[Publications] 三好秀明, 竹内正義他7名: "Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephropathy in mice"Horm.Metab.Res.. 34. 371-377 (2002)
[Publications] 岡本珠美, 竹内正義, 菊地誠志他5名: "Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vivo"Biochem.Biophys.Res.Commun.. 297. 419-424 (2002)
[Publications] 菊地誠志, 竹内正義他5名: "Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neuro"J.Neurosci.Res.. 69. 373-381 (2002)
[Publications] 山岸昌一, 竹内正義他4名: "Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its anti-oxidative properties"Biochem.Biophys.Res.Commun.. 296. 877-882 (2002)
[Publications] 古賀康八郎, 竹内正義他5名: "Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction"Int.J.Clin.Pharm.Res.. 22. 23-27 (2002)
[Publications] 佐々木信幸, 竹内正義, 菊地誠志他8名: "Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques"Neurosci.Lett.. 326. 117-120 (2002)
[Publications] 山岸昌一, 佐々木信幸, 菊地誠志, 竹内正義他6名: "Palmitate-induced apoptosis of microvascular endothelial cells and pericytes"Mol.Med.. 8. 179-184 (2002)
[Publications] 山岸昌一, 竹内正義他5名: "Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells"J.Biol.Chem.. 277. 20309-20315 (2002)
[Publications] 竹内正義, 山岸昌一, 山本博: "高血糖とAGE:新しい治療戦略"BIO Clinica 6月臨時増刊号. 18巻7号. 5 (2003)
[Publications] 竹内正義, 山岸昌一, 牧田善二: "糖尿病治療学の進歩V.2型糖尿病治療の実際(3)糖尿病合併症治療薬:AGE阻害薬OPB-9195"日本臨床増刊号:新時代の糖尿病学(3)-病因・診断・治療研究の進歩. 60巻増刊号9. 5 (2002)
[Publications] 渡辺琢夫, 竹内正義他4名: "特集:糖尿病と酸化ストレス高血糖による細胞内酸化ストレス増強機序:終末糖化産物"Diabetes Frontier. 13巻2号. 5 (2002)

2002 Fiscal Year Annual Research Report

神経変性疾患における終末糖化産物(AGE-2構造体)の細胞障害機構の解明

Principal Investigator

竹内 正義 北陸大学, 薬学部, 講師 (20154982)

Research Products

[Publications] 菊地誠志, 竹内正義, 佐々木信幸 他4名: "Glycation-A sweet tempter for neuronal death-"Brain Res.Review. (印刷中). (2003)

[Publications] 竹内正義, 佐々木信幸, 菊地誠志 他10名: "Neurotoxicity of acetaldehyde-derived advanced glycation end-products for cultured cortical neurons"J.Neuropathol.Exp.Neurol.. (印刷中). (2003)

[Publications] 山岸昌一, 竹内正義 他3名: "Leptin stimulates proliferation of microvascular endothelial cells through autocrine vascular endothelial wth factor production-a possible participation of reactive oxygen species in leptin-induced angiogenesis-"Microvas.Res.. (印刷中). (2003)

[Publications] 三浦順之助, 竹内正義 他11名: "AGE downregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J.Diabetes Complicat.. (印刷中). (2003)

[Publications] 米倉秀人, 竹内正義 他11名: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, ad their putative roles in diabetes-induced vascular injury"Biochem.J.. (印刷中). (2003)

[Publications] 菊地誠志, 竹内正義 他7名: "Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons"Brain Res.. 964. 228-236 (2003)

[Publications] 山岸昌一, 竹内正義 他3名: "Leptin up-regulates vascular endothelial growth factor and down-regulates pigment epithelium-derived factor mRNA levels in cultured retinal pericytes"Int.J.Tissue React.. (印刷中). (2003)

[Publications] 山岸昌一, 竹内正義 他4名: "Advanced glycation end products inhibit de novo protein synthesis and induce TGF-β overexpression in proximal tubular cells"Kidney Int.. 63. 464-473 (2003)

[Publications] 山岸昌一, 竹内正義 他4名: "Dilazep hydrochloride, an antiplatelet drug, prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Drugs Exp.Clin.Res.. (印刷中). (2003)

[Publications] 三浦順之助, 竹内正義 他5名: "Serum leveles of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes"J.Diabetes Complicat.. 17. 16-21 (2003)

[Publications] 天野伸治郎, 竹内正義 他9名: "Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes"Biochem.Biophys.Res.Commun.. 299. 183-188 (2002)

[Publications] 岡本珠美, 竹内正義 他7名: "Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin"FASEB J.. 16. 1928-1930 (2002)

[Publications] Petrova R, 竹内正義 他12名: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J.Mol.Cell.Cardiol.. 34. 1425-1431 (2002)

[Publications] 古賀康八郎, 竹内正義 他7名: "CS-866, a New angiotensin II type 1 receptor antagonist, Ameliorates glomerular anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Mol.Med.. 8. 591-599 (2002)

[Publications] 菊地誠志, 竹内正義 他5名: "Detection of N-(carboxymethyl)lysine (CML) and non-CML advanced glycation end products in the anterior horn of amyotrophic lateral sclerosis spinal cord"Amyotroph.Lateral Scler.Other Motor Neuron Disord.. 3. 63-68 (2002)

[Publications] 山岸昌一, 竹内正義 他4名: "Beraprost sodium, a prostaglandin I_2 analogue, protects against advanced glycation end products-induced injury in cultured retinal pericytes"Mol.Med.. 8. 546-550 (2002)

[Publications] 三好秀明, 竹内正義 他7名: "Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephropathy in mice"Horm.Metab.Res.. 34. 371-377 (2002)

[Publications] 岡本珠美, 竹内正義, 菊地誠志 他5名: "Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vivo"Biochem.Biophys.Res.Commun.. 297. 419-424 (2002)

[Publications] 菊地誠志, 竹内正義 他5名: "Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neuro"J.Neurosci.Res.. 69. 373-381 (2002)

[Publications] 山岸昌一, 竹内正義 他4名: "Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its anti-oxidative properties"Biochem.Biophys.Res.Commun.. 296. 877-882 (2002)

[Publications] 古賀康八郎, 竹内正義 他5名: "Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction"Int.J.Clin.Pharm.Res.. 22. 23-27 (2002)

[Publications] 佐々木信幸, 竹内正義, 菊地誠志 他8名: "Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques"Neurosci.Lett.. 326. 117-120 (2002)

[Publications] 山岸昌一, 佐々木信幸, 菊地誠志, 竹内正義 他6名: "Palmitate-induced apoptosis of microvascular endothelial cells and pericytes"Mol.Med.. 8. 179-184 (2002)

[Publications] 山岸昌一, 竹内正義 他5名: "Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells"J.Biol.Chem.. 277. 20309-20315 (2002)

[Publications] 竹内正義, 山岸昌一, 山本博: "高血糖とAGE:新しい治療戦略"BIO Clinica 6月臨時増刊号. 18巻7号. 5 (2003)

[Publications] 竹内正義, 山岸昌一, 牧田善二: "糖尿病治療学の進歩V.2型糖尿病治療の実際(3)糖尿病合併症治療薬:AGE阻害薬OPB-9195"日本臨床増刊号:新時代の糖尿病学(3)-病因・診断・治療研究の進歩. 60巻増刊号9. 5 (2002)

[Publications] 渡辺琢夫, 竹内正義 他4名: "特集:糖尿病と酸化ストレス 高血糖による細胞内酸化ストレス増強機序:終末糖化産物"Diabetes Frontier. 13巻2号. 5 (2002)

竹内正義北陸大学, 薬学部, 講師 (20154982)

[Publications] 菊地誠志, 竹内正義, 佐々木信幸他4名: "Glycation-A sweet tempter for neuronal death-"Brain Res.Review. (印刷中). (2003)

[Publications] 竹内正義, 佐々木信幸, 菊地誠志他10名: "Neurotoxicity of acetaldehyde-derived advanced glycation end-products for cultured cortical neurons"J.Neuropathol.Exp.Neurol.. (印刷中). (2003)

[Publications] 山岸昌一, 竹内正義他3名: "Leptin stimulates proliferation of microvascular endothelial cells through autocrine vascular endothelial wth factor production-a possible participation of reactive oxygen species in leptin-induced angiogenesis-"Microvas.Res.. (印刷中). (2003)

[Publications] 三浦順之助, 竹内正義他11名: "AGE downregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J.Diabetes Complicat.. (印刷中). (2003)

[Publications] 米倉秀人, 竹内正義他11名: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, ad their putative roles in diabetes-induced vascular injury"Biochem.J.. (印刷中). (2003)

[Publications] 菊地誠志, 竹内正義他7名: "Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons"Brain Res.. 964. 228-236 (2003)

[Publications] 山岸昌一, 竹内正義他3名: "Leptin up-regulates vascular endothelial growth factor and down-regulates pigment epithelium-derived factor mRNA levels in cultured retinal pericytes"Int.J.Tissue React.. (印刷中). (2003)

[Publications] 山岸昌一, 竹内正義他4名: "Advanced glycation end products inhibit de novo protein synthesis and induce TGF-β overexpression in proximal tubular cells"Kidney Int.. 63. 464-473 (2003)

[Publications] 山岸昌一, 竹内正義他4名: "Dilazep hydrochloride, an antiplatelet drug, prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Drugs Exp.Clin.Res.. (印刷中). (2003)

[Publications] 三浦順之助, 竹内正義他5名: "Serum leveles of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes"J.Diabetes Complicat.. 17. 16-21 (2003)

[Publications] 天野伸治郎, 竹内正義他9名: "Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes"Biochem.Biophys.Res.Commun.. 299. 183-188 (2002)

[Publications] 岡本珠美, 竹内正義他7名: "Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin"FASEB J.. 16. 1928-1930 (2002)

[Publications] Petrova R, 竹内正義他12名: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J.Mol.Cell.Cardiol.. 34. 1425-1431 (2002)

[Publications] 古賀康八郎, 竹内正義他7名: "CS-866, a New angiotensin II type 1 receptor antagonist, Ameliorates glomerular anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats"Mol.Med.. 8. 591-599 (2002)

[Publications] 菊地誠志, 竹内正義他5名: "Detection of N-(carboxymethyl)lysine (CML) and non-CML advanced glycation end products in the anterior horn of amyotrophic lateral sclerosis spinal cord"Amyotroph.Lateral Scler.Other Motor Neuron Disord.. 3. 63-68 (2002)

[Publications] 山岸昌一, 竹内正義他4名: "Beraprost sodium, a prostaglandin I_2 analogue, protects against advanced glycation end products-induced injury in cultured retinal pericytes"Mol.Med.. 8. 546-550 (2002)

[Publications] 三好秀明, 竹内正義他7名: "Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephropathy in mice"Horm.Metab.Res.. 34. 371-377 (2002)

[Publications] 岡本珠美, 竹内正義, 菊地誠志他5名: "Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vivo"Biochem.Biophys.Res.Commun.. 297. 419-424 (2002)

[Publications] 菊地誠志, 竹内正義他5名: "Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neuro"J.Neurosci.Res.. 69. 373-381 (2002)

[Publications] 山岸昌一, 竹内正義他4名: "Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its anti-oxidative properties"Biochem.Biophys.Res.Commun.. 296. 877-882 (2002)

[Publications] 古賀康八郎, 竹内正義他5名: "Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction"Int.J.Clin.Pharm.Res.. 22. 23-27 (2002)

[Publications] 佐々木信幸, 竹内正義, 菊地誠志他8名: "Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques"Neurosci.Lett.. 326. 117-120 (2002)

[Publications] 山岸昌一, 佐々木信幸, 菊地誠志, 竹内正義他6名: "Palmitate-induced apoptosis of microvascular endothelial cells and pericytes"Mol.Med.. 8. 179-184 (2002)

[Publications] 山岸昌一, 竹内正義他5名: "Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells"J.Biol.Chem.. 277. 20309-20315 (2002)

[Publications] 渡辺琢夫, 竹内正義他4名: "特集:糖尿病と酸化ストレス高血糖による細胞内酸化ストレス増強機序:終末糖化産物"Diabetes Frontier. 13巻2号. 5 (2002)