Roles of neural metabolic signaling pathway in transitional mechanism to AD

• Project/Area Number: 17H02188
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: Akiko Taguchi 国立研究開発法人国立長寿医療研究センター, 統合加齢神経科学研究部, 部長 (80517186)
• Co-Investigator(Kenkyū-buntansha): 福井 裕介 国立研究開発法人国立長寿医療研究センター, 統合加齢神経科学研究部, 研究員 (60824802) ; 田之頭 大輔 国立研究開発法人国立長寿医療研究センター, 統合加齢神経科学研究部, 研究員 (80724575) ; 王 蔚 国立研究開発法人国立長寿医療研究センター, 統合加齢神経科学研究部, 研究員 (00845167)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 糖尿病 / 糖代謝調節 / 脳 / 認知機能 / 加齢 / 糖代謝調節経路 / アルツハイマー病 / 脳代謝調節経路 / 認知機能障害 / インスリンシグナル / 認知症 / 栄養 / 運動 / 老化 / インスリン受容体基質 / 代謝 / 痴呆 / 脳神経疾患 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We found that1) type2 diabetes (T2DM)-induced memory decline accompanied by alterations in glucose metabolism-related signaling components in the hippocampus is provoked by an amyloid beta (Aβ)-independent mechanism, 2) type1 diabetes (T1DM)-induced memory deficit arises independently of the modification of glucose metabolism-related signaling factors and independently of Aβ, 3) hippocampal alterations in glucose metabolism-related signaling occur when middle-aged novel AD model mice show cognitive decline, 4) T2DM additively exacerbates cognitive impairment and alterations in hippocampal glucose metabolism-related signaling in middle-aged novel AD model mice, and 5) aged mice that have normal glucose metabolism display Aβ-unrelated memory impairment accompanied by alterations in hippocampal glucose metabolism-related signaling as well as T2DM model mice show.

Academic Significance and Societal Importance of the Research Achievements

本研究は、脳の糖代謝調節経路とAβ非依存的認知機能低下の関係および同経路とAβの関係を明らかにした点で学術的意義が深い。これらの詳細なメカニズムについての今後の検討により、認知機能障害の新たな予防・治療法の開発に貢献する可能性がある。

Research Products

• [Journal Article] 代謝・神経機能障害と脳内インスリンシグナル；The relations between neural insulin signaling and metabolic and neural dysfunctions (2019)
  • Author(s): 田口明子
  • Journal Title: 日本老年医学会誌 Volume: 56 Pages: 234-240
  • Peer Reviewed
• [Journal Article] Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease. (2019)
  • Author(s): Tanokashira D, Fukuokaya W, Taguchi A.
  • Journal Title: Neural Regen Res. Volume: Volume 14, Issue 8 Issue: 8 Pages: 1330-1334
  • DOI: 10.4103/1673-5374.253535
  • Peer Reviewed / Open Access
• [Journal Article] Serine Phosphorylation of IRS1 Correlates with Aβ-Unrelated Memory Deficits and Elevation in Aβ Level Prior to the Onset of Memory Decline in AD (2019)
  • Author(s): Wang W, Tanokashira D, Fukui Y, Maruyama M, Kuroiwa C, Saito T, SaidoTC and Taguchi A
  • Journal Title: Nutrients Volume: 11(8) Issue: 8 Pages: 1942-1942
  • DOI: 10.3390/nu11081942
  • Peer Reviewed / Open Access
• [Journal Article] A Unique Case with Oral Dyskinesia, Chorea, Ataxia, and Mild Cognitive Impairment with Caudate Atrophy and Characteristic Brain Calcifications (2018)
  • Author(s): Hishikawa N, Fukui Y, Sato K, Takemoto M, Yamashita T, Ohta Y, Abe K.
  • Journal Title: Internal Medicine Volume: 57 Issue: 16 Pages: 2399-2402
  • DOI: 10.2169/internalmedicine.9454-17
  • NAID: 130007433443
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-08-15
  • Peer Reviewed
• [Journal Article] 脳インスリンシグナルと認知機能障害 (2018)
  • Author(s): 田口明子
  • Journal Title: 医療の広場 Volume: 58 (5) Pages: 4-6
• [Journal Article] Metformin treatment am,eliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1 (2018)
  • Author(s): Tanokashira D , Kurata E, Fukuokaya W, Kawabe K, Takeuchi H, Kashiwada M, Nakazato M, Taguchi A
  • Journal Title: FEBS Open Bio. Volume: 18;8(7) Issue: 7 Pages: 1104-1118
  • DOI: 10.1002/2211-5463.12436
  • Peer Reviewed / Open Access
• [Journal Article] Clinical predictors of Alzheimer's disease progression (2018)
  • Author(s): Hishikawa N, Fukui Y, Takemoto M, Sato K, Shang J, Yamashita T, Ohta Y, Abe K.
  • Journal Title: Geriatr Gerontol Int. Volume: 18(6) Issue: 6 Pages: 929-936
  • DOI: 10.1111/ggi.13286
  • Peer Reviewed
• [Journal Article] Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain. (2018)
  • Author(s): Shang J, Yan H, Jiao Y, Ohta Y, Liu X, Li X, Morihara R, Nakano Y, Fukui Y, Shi X, Huang Y, Feng T, Takemoto M, Sato K, Hishikawa N, Yamashita T, Abe K.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 27(8) Issue: 8 Pages: 2096-2105
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.012
  • Peer Reviewed
• [Journal Article] Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with the change of mitochondrial fission and fusion proteins expression in a novel mouse model (2018)
  • Author(s): Feng T, Yamashita T, Zhai Y, Shang J, Nakano Y, Morihara R, Fukui Y, Hishikawa N, Ohta Y, Abe K
  • Journal Title: Brain Res. Volume: 1696 Pages: 63-70
  • Peer Reviewed
• [Journal Article] Neuroprotective Effects of Tocovid Pretreatment in a Mouse Stroke Model (2018)
  • Author(s): Jiao Y, Shang J, Ohta Y, Yan H, Liu X, Li X, Morihara R, Nakano Y, Fukui Y, Shi X, Huang Y, Feng T, Takemoto M, Sato K, Hishikawa N, Yamashita T, Abe K
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 27(8) Issue: 8 Pages: 2166-2174
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.014
  • Peer Reviewed
• [Journal Article] Antineuroinflammatory Effect of SMTP-7 in Ischemic Mice (2018)
  • Author(s): Huang Y, Ohta Y, Shang J, Morihara R, Nakano Y, Fukui Y, Liu X, Shi X, Feng T, Yamashita T, Sato K, Takemoto M, Hishikawa N, Suzuki E, Hasumi K, Abe K
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 27(11) Pages: 3084-3094
  • Peer Reviewed
• [Journal Article] Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice (2018)
  • Author(s): Morihara R, Yamashita T, Liu X, Nakano Y, Fukui Y, Sato K, Ohta Y, Hishikawa N, Shang J, Abe K
  • Journal Title: J Neurosci Res. Volume: 96(10) Issue: 10 Pages: 1707-1716
  • DOI: 10.1002/jnr.24270
  • Peer Reviewed
• [Journal Article] Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling (2018)
  • Author(s): Shi X, Ohta Y, Shang J, Morihara R, Nakano Y, Fukui Y, Liu X, Feng T, Huang Y, Sato K, Takemoto M, Hishikawa N, Yamashita T, Suzuki E, Hasumi K, Abe K
  • Journal Title: J Neurosci Res. Volume: 96(12) Issue: 12 Pages: 1887-1899
  • DOI: 10.1002/jnr.24326
  • Peer Reviewed
• [Journal Article] 高齢者糖尿病におけるアルツハイマー病の発症機構と病態特性：脳インスリンシグナル関与の可能性 (2018)
  • Author(s): 田口明子、櫻井 孝
  • Journal Title: 月刊 糖尿病 Volume: 112, 10(7) Pages: 38-42
  • Peer Reviewed
• [Journal Article] Detecting spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography. (2017)
  • Author(s): Fukui Y, Hishikawa N, Sato K, Nakano Y, Morihara R, Shang J, Takemoto M, Ohta Y, Yamashita T, Abe K.
  • Journal Title: Neurosci Res. Volume: Epub ahead of print Pages: 58-63
  • DOI: 10.1016/j.neures.2017.11.005
  • Peer Reviewed
• [Journal Article] Social isolation suppresses actin dynamics and synaptic plasticity through ADF/cofilin inactivation in the developing rat barrel cortex (2017)
  • Author(s): Tada H, Miyazaki T, Takemoto K, Jitsuki S, Nakajima W, Koide M, Yamamoto N, Taguchi A, Kawai H, Komiya K, Suyama K, Abe H, Sano A, Takahashi T.
  • Journal Title: Sci. Rep Volume: 7 Issue: 1 Pages: 8471-8471
  • DOI: 10.1038/s41598-017-08849-3
  • Peer Reviewed / Open Access
• [Journal Article] 糖尿病治療薬アクトスの認知症への応用 (2017)
  • Author(s): 田之頭大輔、田口明子
  • Journal Title: Medical Science Digest. Volume: 43(10) Pages: 2-4
  • Peer Reviewed
• [Presentation] Modification of hippocampal IRS1 via Serine Phosphorylation Correlates with Aβ-Unrelated Memory Deficits (2020)
  • Author(s): Wei Wang, Daisuke Tanokashira, Yusuke Fukui, Megumi Maruyama, Chiemi Kuroiwa, Takashi Saito, Takaomi C.Saido and Akiko Taguchi
  • Organizer: Adult Neurogenesis Meeting 2020, Sendai, Japan
• [Presentation] Metformin enhances adult neurogenesis and memory function through hippocampal IRS1 signaling independent of the hypoglycemic effect (2019)
  • Author(s): Akiko Taguchi
  • Organizer: 10th World Gene Convention. Qingdao, China
  • Int'l Joint Research / Invited
• [Presentation] Antidiabetic medication enhances neurogenesis and memory function via hippocampal insulin signaling (2019)
  • Author(s): Akiko Taguchi
  • Organizer: 2019 International Conference on Biotechnology and Bioengineering. Poznan, Poland
  • Int'l Joint Research / Invited
• [Presentation] Metformin enhances neurogenesis and memory function via hippocampal insulin signaling independent of the hypoglycemic effect (2019)
  • Author(s): Akiko Taguchi
  • Organizer: 8th Annual World Congress of Advanced Materials. Osaka, Japan
  • Int'l Joint Research / Invited
• [Presentation] Metformin enhances neurogenesis and memory function via hippocampal insulin signaling independent of the hypoglycemic effect (2019)
  • Author(s): Akiko Taguchi
  • Organizer: 17th Annual Congress of International Drug Discovery Science and Technology. Kyoto, Japan
  • Int'l Joint Research / Invited
• [Presentation] Phosphorylation of specific serine sites on hippocampal insulin receptor substrate 1 is associated with Alzheimer's disease-unrelated memory deficit and -related pathology (2019)
  • Author(s): Daisuke Tanokashira, Yusuke Fukui, Wei Wang, Megumi Maruyama, Chiemi Kuroiwa, Takashi Saito, Takaomi C. Saido, Akiko Taguchi
  • Organizer: Society for Neuroscience 2019, Chicago, USA
  • Int'l Joint Research
• [Presentation] アミロイドβ関連/非関連認知機能低下と脳インスリンシグナル ―― 認知症発症既存仮説 vs.多様な潜在的機構 ―― (2019)
  • Author(s): 田口明子
  • Organizer: 第2回B6J Aged研究会
  • Invited
• [Presentation] 糖代謝変容と高次脳機能障害を結ぶ潜在的経路としての脳インスリンシグナルの役割 (2019)
  • Author(s): 田口明子
  • Organizer: 第11回Stroke Science Academy, 福岡市、日本
  • Invited
• [Presentation] 2型糖尿病による海馬IRSシグナル変化とアルツハイマー病態との連関 (2019)
  • Author(s): 田之頭大輔、王 蔚、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第28回海馬と高次脳機能学会 東京、日本
• [Presentation] セリンリン酸化を介した海馬IRS1シグナルと認知機能障害の関係についての検討 (2019)
  • Author(s): 王 蔚、田之頭大輔、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第28回海馬と高次脳機能学会 東京、日本
• [Presentation] 2型糖尿病が海馬IRSシグナルおよびアルツハイマー病態へ与える影響 (2019)
  • Author(s): 田之頭大輔、王 蔚、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第34回日本糖尿病合併症学会 大阪、日本
• [Presentation] 認知機能障害発症における海馬IRS1セリンリン酸化の役割 (2019)
  • Author(s): 王 蔚、田之頭大輔、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第34回日本糖尿病合併症学会 大阪、日本
• [Presentation] 2型糖尿病による海馬IRSシグナルの変化とアルツハイマー病態増悪化との連関 (2019)
  • Author(s): 田之頭大輔、王 蔚、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第38回日本認知症学会 東京、日本
• [Presentation] 認知機能低下における海馬IRS1セリンリン酸化の役割 (2019)
  • Author(s): 王蔚、田之頭大輔、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第42回日本分子生物学会 福岡市、日本
• [Presentation] 海馬IRSシグナルを介した糖尿病によるアルツハイマー病増悪化機構 (2019)
  • Author(s): 田之頭大輔、王 蔚、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第34回日本糖尿病・肥満動物学会, 群馬県高崎市, 日本
• [Presentation] 認知機能低下におけるセリンリン酸化を介した海馬IRS1シグナルの変化 (2019)
  • Author(s): 王 蔚、田之頭大輔、福井裕介、丸山めぐみ、黒岩智恵美、斉藤貴志、西道隆臣、田口明子
  • Organizer: 第34回日本糖尿病・肥満動物学会, 群馬県高崎市, 日本
• [Presentation] 糖尿病によるアルツハイマー病態増悪化メカニズムの検討 (2018)
  • Author(s): 田之頭大輔、徳永暁憲、多田敬典、佐治多美子、柏田舞波、竹井喜美、佐藤駿介、斉藤貴志、西道隆臣、田口明子.
  • Organizer: 第32回日本糖尿病肥満動物学会
• [Presentation] 糖尿病モデル動物を用いた認知機能障害発症機構の解析. (2018)
  • Author(s): 徳永暁憲、多田敬典、田之頭大輔、佐治多美子、柏田舞波、竹井喜美、佐藤駿介、斉藤貴志、西道隆臣、田口明子.
  • Organizer: 第32回日本糖尿病肥満動物学会
• [Presentation] メトフォルミンが海馬依存的認知機能へ与える影響についての検討. (2018)
  • Author(s): 今井萌乃、田之頭大輔、倉田栄子、福岡屋航、柏田舞波、中里雅光、田口明子.
  • Organizer: 第32回日本糖尿病肥満動物学会
• [Presentation] 糖尿病に伴う脳内糖代謝シグナル活性異常を介したシナプスを起点とする認知機能障害誘導メカニズムの解析. (2018)
  • Author(s): 多田敬典、徳永暁憲、田之頭大輔、柏田舞波、佐治多美子、田口明子.
  • Organizer: 第95回日本生理学会大会
• [Presentation] 糖尿病と認知症を結ぶ潜在的経路としての脳インスリンシグナルの機能. (2017)
  • Author(s): 田口明子.
  • Organizer: 第30回日本老年学会総会、第59回日本老年医学会学術集会
  • Invited
• [Presentation] 糖尿病関連疾患として捉える認知症の誘導機構における脳インスリンシグナルの関与. (2017)
  • Author(s): 田口明子.
  • Organizer: 関西医科大学Diabetes Research Forum
  • Invited
• [Presentation] Neural insulin signaling correlates with diabetes-related cognitive impairment. (2017)
  • Author(s): Daisuke Tanokashira, Wataru Fukuokaya, Akinori Tokunaga, Tamiko Saji, Eiko Kurata, and Akiko Taguchi.
  • Organizer: Cell Symposia-Metabolic Disease Therapies
  • Int'l Joint Research
• [Presentation] Altered neural insulin signaling correlates with both age and diabetes-related cognitive impairment. (2017)
  • Author(s): Akiko Taguchi.
  • Organizer: The International Symposium on Dementia 2017
  • Int'l Joint Research / Invited
• [Presentation] Analysis of synaptic insulin signaling in the hippocampus and prefrontal cortex in diabetes-associated cognitive impairment. (2017)
  • Author(s): Tada H, Tokunaga A, Tanokashira D, Kashiwada M, Saji T, Imai M, Taguchi A.
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Mechanisms linking between impaired hippocampal insulin signaling and diabetes-associated cognitive dysfunction. (2017)
  • Author(s): Tokunaga A, Tada H, Tanokashira D, Saji T, Kashiwada M, Taguchi A.
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] 糖尿病に付随する脳インスリンシグナルの変容がアルツハイマー病態に与える影響. (2017)
  • Author(s): 田之頭大輔、徳永暁憲、多田敬典、佐治多美子、柏田舞波、竹井喜美、佐藤駿介、斉藤貴志、西道隆臣、田口明子.
  • Organizer: 第２６回海馬と高次脳機能学会
• [Presentation] 糖尿病モデル動物を用いた認知機能障害発症機序の解析. (2017)
  • Author(s): 徳永暁憲、多田敬典、田之頭大輔、佐治多美子、柏田舞波、田口明子.
  • Organizer: 第２６回海馬と高次脳機能学会
• [Presentation] 糖尿病による脳インスリン様シグナルを介したアルツハイマー病態増悪化機構の検討. (2017)
  • Author(s): 田之頭大輔、徳永暁憲、多田敬典、佐治多美子、柏田舞波、竹井喜美、斉藤貴志、西道隆臣、田口明子.
  • Organizer: 第32回日本糖尿病合併症学会
• [Presentation] 神経細胞新生に対する糖尿病薬の効果についての検討 The effect of diabetes drug on adult hippocampal neurogenesis. (2017)
  • Author(s): 田之頭大輔、福岡屋航、倉田栄子、中里雅光、田口明子.
  • Organizer: 第13回成体脳のニューロン新生懇談会
• [Presentation] 糖尿病に伴う脳インスリン様シグナル変容がアルツハイマー病態に与える影響. (2017)
  • Author(s): 田之頭大輔、徳永暁憲、多田敬典、佐治多美子、柏田舞波、竹井喜美、斉藤貴志、西道隆臣、田口明子.
  • Organizer: 第36回認知症学会学術集会