Characterization and clinical application of endogenous Alzheimer's disease-suppressing factor

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390059
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: MATSUOKA Masaaki 東京医科大学, 医学部, 教授 (70222297)
• Co-Investigator(Kenkyū-buntansha): IWAMOTO Toshihiko 東京医科大学, 医学部, 兼任教授 (10246168) ; UMAHARA Takahiko 東京医科大学, 医学部, 准教授 (70266477)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: アルツハイマー病 / 神経細胞死 / ヒューマニン

Research Abstract

A new Alzheimer's disease (AD)-suppressive factor EH has been biologically examined. First, it was found that EH concentration in the cerebrospinal fluid is 1-5nM in humans. Second, intraperitoneal administration of EH ameliorates dementia of mice, caused by scopolamine, a muscarinic acetylcholine receptor blocker.. Combined with foregoing findings, these results suggest that EH, rather than Humanin, plays a central role in vivo as an AD-suppressive factor.. Furthermore, EH concentrations in the cerebrospinal fluids of AD patients appear to be lower than those of normal controls. Finally, it was found that EHIbeta inhibits secretion of into extracellular space and EHIsigma is secreted into the extracellular space and inhibits EH activity.

Research Products

• [Journal Article] A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity (2014)
  • Author(s): Hashimoto Y, Matsuoka M
  • Journal Title: J Neurochem
  • DOI: 10.1111/jnc.12717
• [Journal Article] KCTD20, a relative of BTBD10, is a positive regulator of Akt (2013)
  • Author(s): Nawa M, Matsuoka M
  • Journal Title: BMC Biochem Volume: (in press)
• [Journal Article] SH3-binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide Humanin by inhibiting c-Jun NH2-teminal kinase (2013)
  • Author(s): Takeshita Y, Hashimoto Y, Nawa M, Uchino H, Matsuoka M
  • Journal Title: J Biol Chem Volume: 288 Pages: 24691-24704
  • DOI: 10.1074/jbc.M113.469692
• [Journal Article] Secreted calmodulin-like skin protein ameliorates scopolamine-induced memory impairment (2013)
  • Author(s): Hayashi M, Tajima H, Hashimoto Y, Matsuoka M
  • Journal Title: Neuroreport
• [Journal Article] Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis (2013)
  • Author(s): Furuta N, Makioka K, Fujita Y, Ikeda M, Takatama M, Matsuoka M, Okamoto K
  • Journal Title: Neuropathology Volume: 33 Pages: 397-404
  • DOI: 10.1111/neup.12010
• [Journal Article] The JNK/c-jun signaling axis contributes to the TDP-43-induced cell death (2013)
  • Author(s): Suzuki H, Matsuoka M
  • Journal Title: Mol Cell Biochem Volume: 372 Pages: 241-248
• [Journal Article] D-amino acid oxidase controls motoneuron degeneration through D-serine (2012)
  • Author(s): Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konnno R, Matsuoka M, Hamase K, Aiso S
  • Journal Title: Proc Natl Acad Sci USA Volume: 109 Pages: 627-632
• [Journal Article] Reduced expression of BTBD10, an Akt activator, leads to motor neuron death (2012)
  • Author(s): Nawa M, Kage-Nakadai E, Aiso S, Okamoto K, Mitani S, Matsuoka M
  • Journal Title: Cell Death Differ Volume: 19 Pages: 1398-1407
• [Journal Article] MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid beta precursor protein and presenilins (2012)
  • Author(s): Tachi N, Hashimoto Y, Matsuoka M
  • Journal Title: Biochem J Volume: 442 Pages: 413-422
• [Journal Article] TDP-43 toxicity is mediated by the unfolded protein response-unrelated induction of C/EBP homologous protein expression (2012)
  • Author(s): Suzuki H, Matsuoka M
  • Journal Title: J Neurosci Res Volume: 90 Pages: 641-647
• [Journal Article] Overexpression of TDP-43 causes partially p53-dependent G2/M arrest and p53-independent cell death in HeLa cells (2012)
  • Author(s): Lee K, Suzuki H, Aiso S, Matsuoka M
  • Journal Title: Neurosci Lett Volume: 506 Pages: 271-276
• [Journal Article] Amyotrophic lateral sclerosis-linked mutant VAPB enhances TDP-43-induced motor neuronal toxicity (2011)
  • Author(s): Suzuki H, Matsuoka M
  • Journal Title: J Neurochem Volume: 119 Pages: 1099-1107
• [Journal Article] VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin (2011)
  • Author(s): Rossini L, Hashimoto Y, Suzuki H, Kurita M, Gianfriddo M, Scali C, Roncarati R, Franceschini D, Pollio G, Trabalzini L, Terstappen GC, Matsuoka M, Caricasole A
  • Journal Title: FASEB J Volume: 25 Pages: 1983-2000
• [Journal Article] TDP-43-induced death is associated with altered regulation of BIM and Bcl-xL and attenuated by caspase-mediated TDP-43 cleavage (2011)
  • Author(s): Suzuki H, Lee K, Matsuoka M
  • Journal Title: J Biol Chem Volume: 286 Pages: 13171-13183
• [Journal Article] Humanin signal for Alzheimer's disease (2011)
  • Author(s): Matsuoka M
  • Journal Title: A review.J Alzheimers Dis Volume: 24 Suppl 2 Pages: 27-32
• [Journal Article] Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer' s disease models via the heterotrimeric Humanin receptor
  • Author(s): Hashimoto Y, Nawa M, Kurita M, Tokizawa M, Iwamatsu A, Matsuoka M
  • Journal Title: Cell Death Dis Mar Volume: 21;4 Pages: e555
  • DOI: 10.1038/cddis.2013.80