A role of insulin signal impairment in the pathogenesis of Alzheimer disease

• Project/Area Number: 20590990
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: IKEUCHI Takeshi Niigata University, 脳研究所, 助教 (20372469)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アルツハイマー病 / 認知症 / 糖尿病 / インスリンシグナル伝達 / 脳神経疾患 / 神経科学 / 脂質 / 薬理学

Research Abstract

Insulin resistance caused by diabetes is now recognized as risk factor of Alzheimer disease (AD). We conducted a research to verify a role of insulin signal impairment in AD pathogenesis and here provide following findings. i) increase of insulin in culture medium leads to enhanced production of β-amyloid (Aβ). ii) overproduction of Aβ induces abnormal phosphorylation of tau, iii) insulin signal transduction is impaired by overproduction of Aβ. These findings suggest that heperinsulinemia may accelerates AD pathogenesis and insulin signal transduction may play a role in Aβ-induced tau phosphorylation.

Research Products

• [Journal Article] Dementia Geriat Cogn Disord (2010)
  • Author(s): Ikeuchi T, Hirayama S, Miida T, Fukamachi I, Tokutake T, Ebinuma H, Takubo K, Kaneko H, Kasuga K, Kakita A, Takahashi H, Bujo H, Saito Y, Nishizawa M.
  • Journal Title: 30 Pages: 28-32
  • Peer Reviewed
• [Journal Article] Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, parkinsonism and motor neuron disease : a distinct clinicopathological and biochemical disease entity. (2010)
  • Author(s): Fu Y, Nishihira Y, Kuroda S, Toyoshima Y, Ishihara T, Shinozaki M, Miyashita A, Piao YS, Tan CF, Tani T, Koide R, Iwanaga K, Tsujihata M, Onodera O, Kuwano R, Nishizawa M, Kakita A, Ikeuchi T, Takahashi H.
  • Journal Title: Acta Neuropathologica 120 Pages: 21-32
  • Peer Reviewed
• [Journal Article] Differential levels of α-synuclein, β-amyloid, and tau in cerebrospinal fluid between patients with dementia with Lewy bodies and Alzheimer disease. (2010)
  • Author(s): Kasuga K, Tokutake T, Ishikawa A, Uchiyama T, Tokuda T, Onodera O, Nishizawa M, Ikeuchi T.
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry 81 Pages: 608-610
  • Peer Reviewed
• [Journal Article] Alzheimer's disease : Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration. (2010)
  • Author(s): Okazaki K, Fu Y-J, Nishihira Y, Endo M, Fukushima T, Ikeuchi T, Okamoto K, Onodera O, Nishizawa M, Takahashi H.
  • Journal Title: Neuropathology 30 Pages: 140-148
  • NAID: 10029320298
  • Peer Reviewed
• [Journal Article] Increased levels of soluble LR11 in cerebrospinal fluid of patients with Alzheimer disease (2010)
  • Author(s): Ikeuchi, et al.
  • Journal Title: Dementia and Geriatric Cognitive Disorders Volume: 30 Pages: 28-32
  • Peer Reviewed
• [Journal Article] Differential levels of alpha-synuclein, beta-amyloid, and tau in cerebrospinal fluid between patients with Lewy bodies and Alzheimer disease (2010)
  • Author(s): Kasuga, et al.
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: 81 Pages: 608-610
  • Peer Reviewed
• [Journal Article] Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, parkinsonism and motor neuron disease : a distinct clinicopathological and biochemical disease entity (2010)
  • Author(s): Fu, et al.
  • Journal Title: Acta Neuropathologia Volume: 120 Pages: 21-32
• [Journal Article] Depression and psychiatric symptoms preceding onset of dementia in family with early-onset Alzheimer disease with novel PSEN1-mutation. (2009)
  • Author(s): Kasuga K, Ohno T, Ishihara T, Miyashita A, Kuwano R, Onodera O, Nishizawa M, Ikeuchi T.
  • Journal Title: Journal of Neurology 256 Pages: 1351-1353
  • Peer Reviewed
• [Journal Article] Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. (2009)
  • Author(s): Kasuga K, Shimohata T, Nishimura A, Shiga A, Mizuguchi T, Tokunaga J, Ohno T, Miyashita A, Kuwano R, Matsumoto N, Onodera O, Nishizawa M, Ikeuchi T.
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry 80 Pages: 1050-1052
  • Peer Reviewed
• [Journal Article] The 28-amino acid form of an APLP1-derived Aβ-like peptide is a surrogate marker for Aβ42 production in the central nervous system. (2009)
  • Author(s): Yanagida K, Okochi M, Tagami S, Nakayama T, Kodama TS, Nishitomi K, Jiang J, Mori K, Tatsumi S,T Arai T, Ikeuchi T, Kasuga K, Tokuda T, Masaki Kondo M, Masaki Ikeda M, Kentaro Deguchi K, Hiroaki Kazui H, Tanaka T, Morihara T, Hashimoto R, Kudo T, Steiner H, Haass C, Tsuchiya K, Akiyama H, Kuwano R, Takeda M.
  • Journal Title: EMBO Molecular Medicine 1 Pages: 223-235
  • Peer Reviewed
• [Journal Article] Depression and psychiatric symptoms preceding onset of dementia in family with early-onset Alzheimer disease with novel PSEN1 mutation (2009)
  • Author(s): Kasuga, et al.
  • Journal Title: Journal of Neurology Volume: 256 Pages: 1351-1353
  • Peer Reviewed
• [Journal Article] Selective occurrence of TDP-43 immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease (2009)
  • Author(s): Tan, et al.
  • Journal Title: Acta Neuropathologia Volume: 118 Pages: 553-560
  • Peer Reviewed
• [Journal Article] The 28-amino acid form of an APLP-1 derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system (2009)
  • Author(s): Yanagida, et al.
  • Journal Title: EMBO Molecular Medicine Volume: 1 Pages: 223-235
  • Peer Reviewed
• [Journal Article] Depression and psychiatric symptoms preceding onset of dementia in family with early-onset Alzheimer disease with novel PSEN1 mutation. (2009)
  • Author(s): Kasuga, et al.
  • Journal Title: Journal of Neurology (in press)
  • Peer Reviewed
• [Journal Article] Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. (2009)
  • Author(s): Kasuga, et al.
  • Journal Title: Journal of Neurology, Neurosurgery, and Psychiatry (in press)
  • Peer Reviewed
• [Journal Article] Novel GFAP mutation in patient with adult-onset Alexander disease presenting with spastic ataxia (2009)
  • Author(s): Kaneko, et al.
  • Journal Title: Movement Disorders (in press)
  • Peer Reviewed
• [Presentation] レビー小体型認知症(DLB)の新規バイオマーカー:髄液αシヌクレインのELISA定量 (2010)
  • Author(s): 徳武孝允, 春日健作, 矢島隆二, 石川厚, 内山剛, 徳田隆彦, 西澤正豊, 池内健
  • Organizer: 第29回日本認知症学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-05
• [Presentation] アルツハイマー病患者・髄液中では可溶性LR11が増加する (2010)
  • Author(s): 池内健, 平山哲, 三井田孝, 深町勇, 矢島隆二, 徳武孝允, 春日健作, 金子博之, 田久保耕平, 海老沼宏幸, 武城英明, 西澤正豊
  • Organizer: 第29回日本認知症学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-05
• [Presentation] 遺伝子変異を伴った家族性アルツハイマー病の表現型の比較 (2010)
  • Author(s): 池内健, 他
  • Organizer: 第50回日本神経学会
  • Place of Presentation: 仙台国際センター (宮城県)
  • Year and Date: 2010-05-24
• [Presentation] APOEε4(+)群とε4(-)群との臨床経過,側頭葉内側部萎縮,髄液バイオマーカーの比較 (2010)
  • Author(s): 矢島隆二, 池内健, 春日健作, 徳武孝允, 西澤正豊
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] 健忘主体の臨床徴候を呈するタウ遺伝子R406W変異を伴う家族性認知症 (2010)
  • Author(s): 池内健, 春日健作, 宮下哲典, 川瀬康裕, 杉下守弘, 桑野良三, 西澤正豊
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 仙台
  • Year and Date: 2010-05-20
• [Presentation] βアミロイド依存性タウリン酸化カスケードにおけるインスリンシグナル障害の関与 (2010)
  • Author(s): 徳武孝允, 池内健, 春日健作, 篠崎真, 小野寺理, 西澤正豊
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] 健忘主体の臨床徴候を呈するタウ遺伝子R406W変異を伴う家族性認知症 (2010)
  • Author(s): 池内健, 他
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 東京フォーラム(東京都)
  • Year and Date: 2010-05-20
• [Presentation] アルツハイマー病関連・βアミロイド(Aβ)配列内変異がAβ産生および高次構造に及ぼす影響 (2009)
  • Author(s): 篠崎真, 金子博之, 春日健作, 徳武孝允 ,小野寺理, 西澤正豊, 池内健
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-11
• [Presentation] 健忘主体の特異な臨床型を呈したタウ遺伝子(MAPT)R406W変異を伴う家族性認知症の臨床分子遺伝子学的解析 (2009)
  • Author(s): 池内健, 春日健作, 宮下哲典, 川瀬康裕, 小野寺理, 杉下守弘, 桑野良三, 西澤正豊
  • Organizer: 第28回日本認知症学会
  • Place of Presentation: 仙台
  • Year and Date: 2009-11-21
• [Presentation] レビー小体の大脳皮質におけるαシヌクレイン蓄積とSNCAmRNA発現の検討 (2009)
  • Author(s): 野崎洋明, 石平悠, 金子博之, 豊島靖子, 柿田明美, 高橋均, 小野寺理, 西澤正豊, 池内健
  • Organizer: 第28回日本認知症学会
  • Place of Presentation: 仙台
  • Year and Date: 2009-11-21
• [Presentation] Aβはインスリンシグナルを障害することでタウの過剰リン酸化を引き起こすか? (2009)
  • Author(s): 春日健作, 徳武孝允, 篠崎真, 西澤正豊, 小野寺理, 池内健
  • Organizer: 第28回日本認知症学会
  • Place of Presentation: 仙台
  • Year and Date: 2009-11-20
• [Presentation] 認知症性疾患の髄液バイオマーカーとしてのαシヌクレインの検討 (2009)
  • Author(s): 春日健作, 池内健, 石川厚, 徳田隆彦, 中川正法, 小野寺理, 西澤正豊
  • Organizer: 第50回日本神経学会口演発表
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-24
• [Presentation] 遺伝子変異を伴った家族性アルツハイマー病の表現形の比較 (2009)
  • Author(s): 池内健, 春日健作, 野崎洋明, 石原智彦, 金子博之, 篠崎真, 桑野良三, 小野寺理, 西澤正豊
  • Organizer: 第50回日本神経学会口演発表
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] プレセニリン1変異による難溶性αシヌクレイン蓄積の分子機序 (2008)
  • Author(s): 池内健, 他
  • Organizer: 49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-17
• [Book] Dentatorubral-pallidoluysian atrophy (DRPLA) : clinical and genetic features, and neuroimaging (2008)
  • Author(s): Ikeuchi, et al.
  • Total Pages: 172
  • Publisher: Research Singpost
• [Remarks] ホームページ等