Pathophysiology of Alzheimer's disease and mitochondrial dysfunction

• Project/Area Number: 24591249
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: University of Tsukuba
• Principal Investigator: TAMAOKA Akira 筑波大学, 医学医療系, 教授 (50192183)
• Co-Investigator(Kenkyū-buntansha): TAKUMA Hiroshi 筑波大学, 医学医療系, 講師 (00326258) ; TOMIDOKORO Yasushi 筑波大学, 医学医療系, 講師 (80447250)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アルツハイマー病 / アミロイドβ蛋白 / ミトコンドリア / 酸化ストレス / BACE1 / γ-secretase / アミロイド前駆体蛋白（APP） / APP

Outline of Final Research Achievements

Mitochondrial dysfunction is implicated in the neurodegeneration in Alzheimer’s disease. Accumulation of amyloid β protein (Aβ) in mitochondria is suggested to be responsible for mitochondrial dysfunction. Then, we investigated processing of amyloid precursor protein (APP) in mitochondria in vitro studies.
Microsome and crude mitochondria fractions were obtained from human neuroblastoma SH-SY5Y cells overexpressing Swedish mutant APP by homogenization and centrifugation. By Western blot analysis. components of γ-secretase complex were similarly recovered in microsome and crude mitochondria fractions, and BACE1 was enriched in microsome fraction. After iodixanol gradient fractionation, γ-secretase complex components were recovered mainly in lysosome-enriched fractions. Taking these findings into consideration, it is unlikely that Aβ is generated from APP locally in mitochondria.

Research Products

• [Journal Article] Improvement of gait ability with a short-term intensive gait rehabilitation program using body weight support treadmill training in community dwelling chronic poststroke survivors (2015)
  • Author(s): Takao T, Tanaka N, Iizuka N, Saitou H, Tamaoka A, Yanagi H
  • Journal Title: Journal of Physical Therapy Science Volume: 27 Issue: 1 Pages: 159-163
  • DOI: 10.1589/jpts.27.159
  • NAID: 130004835078
  • ISSN: 0915-5287, 2187-5626
  • Peer Reviewed / Open Access
• [Journal Article] Amyloid beta-protein and lipid rafts: focused on biogenesis and catabolism (2015)
  • Author(s): Araki W, Tamaoka A
  • Journal Title: Front Biosci (Landmark Ed) Volume: 20 Pages: 314-324
  • Peer Reviewed / Open Access
• [Journal Article] Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway. (2014)
  • Author(s): Araki W., Minegishi S., Motoki K., Kume H., Hohjoh H., Araki YM., and Tamaoka A.
  • Journal Title: Mol Neurobiol Volume: 50 Issue: 3 Pages: 1049-1058
  • DOI: 10.1007/s12035-014-8644-6
  • Peer Reviewed
• [Journal Article] Detection of diphenylarsinic acid and its derivatives in human serum and cerebrospinal fluid (2014)
  • Author(s): Ishii K, Itoh Y, Iwasaki N, Shibata Y, Tamaoka A
  • Journal Title: Clin Chim Acta Volume: 431 Pages: 227-231
  • DOI: 10.1016/j.cca.2014.01.029
  • Peer Reviewed
• [Journal Article] LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains. (2014)
  • Author(s): Satoh J, Motohashi N, Kino Y, Ishida T, Yagishita S, Jinnai K, Arai N, Nakamagoe K, Tamaoka A, Saito Y, Arima K.
  • Journal Title: Orphanet J Rare Dis Volume: 9 Issue: 1 Pages: 1-11
  • DOI: 10.1186/1750-1172-9-68
  • Peer Reviewed / Open Access
• [Journal Article] Amelioration of acylcarnitine profile using bezafibrate and riboflavin in a case of adult-onset glutaric acidemia type 2 with novel mutations of the electron transfer flavoprotein dehydrogenase (ETFDH) gene (2014)
  • Author(s): Shioya A, Takuma H, Yamaguchi S, Ishii A, Hiroki M, Fukuda T, Sugie H, Shigematsu Y, Tamaoka A
  • Journal Title: J Neurol Sci Volume: 346(1-2) Issue: 1-2 Pages: 350-352
  • DOI: 10.1016/j.jns.2014.08.040
  • Peer Reviewed / Open Access
• [Journal Article] Sixth nerve palsy associated with obstruction in Dorello's canal, accompanied by nodular type muscular sarcoidosis (2014)
  • Author(s): Shioya A, Takuma H, Shiigai M, Ishii A, Tamaoka A
  • Journal Title: J Neurol Sci pii: S0022-510X(14)00359-1. Volume: 343(1-2) Issue: 1-2 Pages: 203-205
  • DOI: 10.1016/j.jns.2014.05.055
  • NAID: 120007136625
  • Peer Reviewed / Open Access
• [Journal Article] Glossopharyngeal nerve and vagus nerve palsies associated with influenza vaccination (2014)
  • Author(s): Ishii K, Kanazawa T, Tomidokoro Y, Tamaoka A
  • Journal Title: Intern Med Volume: 53(3) Pages: 259-261
  • NAID: 130003392628
  • Peer Reviewed / Open Access
• [Journal Article] Sustained efficacy of apomorphine in Japanese patients with advanced Parkinson's disease (2014)
  • Author(s): Hattori N, Nomoto M, 6500-004 Study Froup
  • Journal Title: Parkinsonism Relat Disord Volume: 20(8) Issue: 8 Pages: 819-823
  • DOI: 10.1016/j.parkreldis.2014.04.008
  • Peer Reviewed / Open Access
• [Journal Article] Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation (2014)
  • Author(s): A. Iwata, K. Nagata, H. Hatsuta, H. Takuma, M. Bundo, K. Iwamoto, A. Tamaoka, S. Murayama, T. Saido and S. Tsuji
  • Journal Title: Hum Mol Genet Volume: 23 Issue: 3 Pages: 648-656
  • DOI: 10.1093/hmg/ddt451
  • Peer Reviewed
• [Journal Article] The CHC22 clathrin-GLUT4 transport pathway contributes to skeletal muscle regeneration (2013)
  • Author(s): Hoshino S, Sakamoto K, Vassilopoulos S, Camus SM, Griffin CA, Esk C, Torres JA, Ohkoshi N, Ishii A, Tamaoka A, Funke BH, Kucherlapati R, Margeta M, Rando TA, Brodsky FM
  • Journal Title: PLoS One Volume: 8(10) Issue: 10 Pages: e77787-e77787
  • DOI: 10.1371/journal.pone.0077787
  • Peer Reviewed
• [Journal Article] A unique mouse model for investigating the properties of amyotrophic lateral sclerosis-associated protein TDP-43, by in utero electroporation. (2013)
  • Author(s): Akamatsu, M., Takuma, H., Yamashita, T., Okada, T., Keino-Masu, K., Ishii, K., Kwak, S., Masu, M., and Tamaoka, A.
  • Journal Title: Neuroscience Research Volume: 77 Issue: 4 Pages: 234-241
  • DOI: 10.1016/j.neures.2013.09.009
  • NAID: 120007130577
  • Peer Reviewed
• [Journal Article] Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid (2013)
  • Author(s): Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, Akiyama H
  • Journal Title: Int J Neurosci Volume: 124(5) Pages: 344-349
  • Peer Reviewed
• [Journal Article] Response to comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells". (2013)
  • Author(s): Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, Aoi T, Watanabe A, Yamada Y, Morizane A, Takahashi J, Ayaki T, Ito H, Yoshikawa K, Yamawaki S, Suzuki S, Watanabe D, Hioki H, Kaneko T, Makioka K, Okamoto K, Takuma H, Tamaoka A, Hasegawa K, Nonaka T, Hasegawa
  • Journal Title: Sci Transl Med. Volume: 5(188) Issue: 188
  • DOI: 10.1126/scitranslmed.3005697
  • Peer Reviewed / Open Access
• [Journal Article] Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons (2013)
  • Author(s): Hosaka A, Araki W, Oda A, Tomidokoro Y, Tamaoka A
  • Journal Title: Neurochem Res Volume: 38 Issue: 3 Pages: 589-600
  • DOI: 10.1007/s11064-012-0956-1
  • Peer Reviewed
• [Journal Article] Reduction ofβ -amyloid accumulation by reticulon 3 in transgenic mice (2013)
  • Author(s): Araki W, Oda A, Motoki K, Hattori K, Itoh M, Yuasa S, Konishi Y, Shin RW, Tamaoka A, Ogino K
  • Journal Title: Curr Alzheimer Res Volume: 10 Pages: 135-142
  • Peer Reviewed
• [Journal Article] Molecular analysis and biochemical classification of TDP-43 proteinopathy (2012)
  • Author(s): Tsuji H
  • Journal Title: Brain Volume: 135(11) Issue: 11 Pages: 3380-91
  • DOI: 10.1093/brain/aws230
  • Peer Reviewed
• [Journal Article] Drug screening for ALS using patient-specific induced pluripotent stem cells (2012)
  • Author(s): Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., Adachi, F., Kondo, T., Okita, K., Asaka, I., Aoi, T., Watanabe, A., Yamada, Y., Morizane, A., Takahashi, J., Ayaki, T., Ito, H., Yoshikawa, K., Yamawaki, S., Suzuki, S., Watanabe, D., Hioki, H., Kaneko, T., Makioka, K., Okamoto, K., Takuma, H., Tamaoka, A., Hasegawa, K., Nonaka, T., Hasegawa, M., Kawata, A., Yoshida, M., Nakahata, T., Takahashi, R., Marchetto, M. C. N., Gage, F. H., Yamanaka, S., and Inoue, H
  • Journal Title: Sci. Transl. Med. Volume: 4 Issue: 145 Pages: 1-8
  • DOI: 10.1126/scitranslmed.3004052
  • Peer Reviewed
• [Journal Article] Neuronal β-amyloid generation is independent of lipid raft association of β-secretase BACE1: Analysis with a palmitoylation-deficient mutant (2012)
  • Author(s): Motoki K, Kume H, Oda A, Tamaoka A, Hosaka A, Kametani F, Araki W
  • Journal Title: Brain and Behavior Volume: 2 Issue: 3 Pages: 270-282
  • DOI: 10.1002/brb3.52
  • Peer Reviewed
• [Presentation] TDP-43 aggregation produced by In utero electroporation and its properties in the mouse motor neurons
  • Author(s): M. AKAMATSU, H. TAKUMA, T. YAMASHITA, T. OKADA, K. ISHII, K. KEINO-MASU, S. KWAK, M. MASU, A. TAMAOKA
  • Organizer: Society for Neuroscience 43th Annual Meeting
  • Place of Presentation: San Diego Convention Center, USA