アルツハイマー病に対する革新的治療法の開発

• Project/Area Number: 17689034
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: 里 直行 Osaka University, 医学系研究科, 寄附講座准教授 (70372612)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥30,680,000 (Direct Cost: ¥23,600,000、Indirect Cost: ¥7,080,000); Fiscal Year 2007: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000); Fiscal Year 2006: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000); Fiscal Year 2005: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
• Keywords: アルツハイマー病 / 遺伝子治療 / 肝細胞増殖因子 / ベータ・アミロイド / 血管

Research Abstract

アルツハイマー病(AD)は認知症の原因疾患として最も多く約半数を占める。また、ADモデルマウスでの脳血管異常、Aβの血管新生阻害作用が報告されている。そこで我々は、血管新生作用、神経細胞保護作用を持つ肝細胞増殖因子(HGF)に着目し、マウスにおけるAβ起因性認知機能障害に対する効果を検討した。マウスの側脳室にAβを投与する認知機能障害モデルを用いた。Aβ投与2週間後にhuman HGF cDNAを投与し超音波を照射する超音波遺伝子導入法で遺伝子導入を行った。遺伝子投与1週間後にY-maze test、Water finding taskの2種類の行動試験を施行し認知機能評価を行ったところ、HGF遺伝子導入群ではいずれの行動試験でも認知機能の改善を認めた。HGF遺伝子導入群では両側海馬歯状回の血管床の回復、酸化ストレスの減少が認められた。synaptophysin染色ではHGF遺伝子導入群でsynaptophysin陽性顆粒の増加を認めた。次にHGFとBDNF(Brain Derived Neurotrophic Factor)について比較検討を行った。BDNFはその多型がエピソード記憶に関与していると報告されている神経栄養因子である。HGF遺伝子導入群に比し、BDNF遺伝子導入群ではWater finding taskでは改善を認めたものの、Y-maze testでは有意な改善を認めなかった。さらに、BDNF遺伝子導入群のみならず、HGF遺伝子導入群においてもBDNFの蛋白、mRNAレベルでの発現上昇を認めた。HGF遺伝子導入は海馬歯状回の血管床の回復、BDNFの発現上昇、酸化ストレスの減少、シナプスの活性化によりマウスにおけるAβによる認知機能障害を改善することが示された。この結果から、アルツハイマー病に対してのHGF遺伝子治療、もしくはHGFを増加させる治療法の可能性が示唆された。

Research Products

• [Journal Article] Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model. (2008)
  • Author(s): TakeucM D, Sato N, Shimamura M, Kurinami H, Takeda S, Shinohara M, Suzuki S, Kojima M, Ogihara T and Morishita R.
  • Journal Title: Gene Therapy in press
  • Peer Reviewed
• [Journal Article] Prevention of amyloid β-induced memory impairment by fluvastatin, associated with the decrease in amyloid β accumulation and oxidative stress inamyloid βinjection mouse model. (2008)
  • Author(s): Kurinami H, Sato N, Shinohara M, Takeuchi D, Takeda S, Shimamura M, Ogihara T and Morishita R.
  • Journal Title: International Journal of Molecular Medicine in press
  • Peer Reviewed
• [Journal Article] The Renin-Angiotensin System, Hypertension and cognitive dysfunction in Alzheimer's Disease: New Therapeutic Potential. (2008)
  • Author(s): Takeda S, Sato N, Morishita R
  • Journal Title: Frontiers in Bioscience 13 Pages: 2253-65
  • Peer Reviewed
• [Journal Article] Involvement of gamma-secretase in postnatal angiogenesis. (2007)
  • Author(s): Hayashi H, Nakagami H, Takami Y, Sato N, Saitoh Y, Nishikawa T, Mori M, Koriyama H, Tamai K, Morishita R, Kaneda Y.
  • Journal Title: Biochem. Biophys. Res. Conunun. 363 Pages: 584-90
  • Peer Reviewed
• [Journal Article] Delayed Post-ischemic Treatment with Fluvastatin Improved Learning and Memory Deficit After Stroke in Rats. (2007)
  • Author(s): Shimamura M, Sato N, Sata, M, Kurinami, H, Takeuchi, D, Wakayama, K, Hayashi, T, Iida, H, Morishita R.
  • Journal Title: Stroke 38 Pages: 3251-8
  • Peer Reviewed
• [Journal Article] Expression of hepatocyte growth factor and c-Met after spinal cord injury in rats. (2007)
  • Author(s): Shimamura M, Sato N, Sata M, Wakayama K, 0gihara T, Morishita R.
  • Journal Title: Brain Res. 1151 Pages: 188-94
  • Peer Reviewed
• [Journal Article] Quantitative measurement of neurological deficit after mild (30 min) transient middle cerebral artery occlusion in rats. (2007)
  • Author(s): Wakayama K, Shimamura M, Sata M, Sato N, Kawakami K, Fukuda H, Tomimatsu T, Ogihara T, Morishita R
  • Journal Title: Brain Res. 1130号 Pages: 181-187
• [Journal Article] Gene Transfer of Hepatocyte Growth Factor Gene Improves Learning and Memory in the Chronic Stage of Cerebral Infarction. (2006)
  • Author(s): Shimamura M, Sato N, Waguri S, Uchiyama Y, Hayashi T, Iida H, Nakamura T, Ogihara T, Kaneda Y, Morishita M
  • Journal Title: Hypertension 47 Pages: 742-751
• [Journal Article] Development of new screening system for Alzheimer Disease, in vitro Aβ sink assay, to identify the dissociation of soluble Aβ from fibrils. (2006)
  • Author(s): Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura M, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R
  • Journal Title: Neuobiology of Disease 22 Pages: 487-495
• [Journal Article] Recent Progress in Cerebrovascular Gene Therapy (2005)
  • Author(s): Sato N, Shimamura M, Morishita R.
  • Journal Title: Current Neurovascular Research. 2・3 Pages: 235-247
• [Journal Article] Gene Therapy for Ischemic Brain Disease with special reference to Vascular Dementia.
  • Author(s): Sato N, Shimamura M, Takeuchi D, Kurinami H, Ogihara T, Morishita R
  • Journal Title: Geriatrics and Gerontology International in press
  • NAID: 10019489400
• [Journal Article] Development of new screening system for Alzheimer Disease, in vitro Aβ sink assay, to identify the dissociation of soluble Aβ from fibrils.
  • Author(s): Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura M, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R.
  • Journal Title: Neuobiology of Disease. (in press)
• [Journal Article] Gene transfer into adult rat spinal cord using naked plasmid DNA and ultrasound microbubbles.
  • Author(s): Shimamura, M., Sato, N., Taniyama, Y., Kurinami, H., Tanaka, H., Takami, T., Ogihara, T., Tohyama, M., Kaneda, Y., Morishita, R.
  • Journal Title: J.Gene Med (in press)
• [Presentation] Gene Transfer of HGF by microbubble-enhanced ultrasound improved Aβ-induced Memory Impairment in Mice (2007)
  • Author(s): Takeuchi D, Sato N, Shimamura M, Kurinami H, Takeda S, Shinohara M, Suzuki S, Kojima M, Ogihara T and Morishita R.
  • Organizer: Neuroscience 2007
  • Place of Presentation: San Diego USA
  • Year and Date: 2007-11-07
• [Presentation] Ultrasound-mediated gene transfer of HGF improved Abeta-induced cognitive impairment in mice associated with upregulation of BDNR recovery of and downregulation of oxidative stress. (2007)
  • Author(s): Takeuchi D, Sato N, Shimamura M, Kurinami H, Takeda S, Shinohara M, Suzuki S, Kojima M, Ogihara T and Morishita R.
  • Organizer: ASGT 10th Annual Meeting
  • Place of Presentation: Seattle USA
  • Year and Date: 2007-05-31
• [Patent(Industrial Property Rights)] Remedy for Alzheimers disease (2007)
  • Inventor(s): 里直行、林真一郎、竹内大亮、森下竜一
  • Industrial Property Rights Holder: 大阪大学、アンジェス MG
  • Filing Date: 2007-05-24
  • Overseas