2013 Fiscal Year Final Research Report
Development of therapeutic strategy for Alzheimer's disease by targeting amyloid precursor protein C99
| Project/Area Number |
23500445
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurochemistry/Neuropharmacology
|
|---|
| Research Institution | Shiga University of Medical Science |
|---|
Principal Investigator |
NISHIMURA Masaki 滋賀医科大学, 分子神経科学研究センター, 准教授 (40322739)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MATSUO Akinori 滋賀医科大学, 分子神経科学研究センター, 助教 (20324585)
|
|---|
| Project Period (FY) |
2011 – 2013
|
| Keywords | アルツハイマー病 / アミロイドβ / ILEI / FAM3C / γセクレターゼ |
|---|
| Research Abstract |
Accumulation of amyloid-b (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b- and g-secretase-mediated sequential proteolysis of Ab precursor protein (APP). Although g-secretase is a major target of therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling. We have identified a secretory protein named ILEI as a negative regulator of Ab production. ILEI destabilized the b-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signaling and g-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its reduction in the brains of AD patients. transgenic over expression of ILEI significantly reduced the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.
|
Research Products
(25 results)
-
[Journal Article] OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin2013
Author(s)
Han J, Jung S, Jang J, Kam TI, Choi H, Kim BJ, Nah J, Jo DG, Nakagawa T, Nishimura M, Jung YK
-
Journal Title
Cell Mol Life Sci
Volume: (in press)
DOI
Peer Reviewed
-
[Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels : a potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease2012
Author(s)
Saito Y, Inoue T, Zhu G, Kimura N, Okada M, Nishimura M, Kimura N, Murayama S, Kaneko S, Shigemoto R, Imoto1 K, Suzuki T
-
Journal Title
Mol Neurodegener
Volume: 7
Pages: 50
Peer Reviewed
-
-
-
-
[Journal Article] Potent amyloidogenicity and pathogenicity of Aβ432011
Author(s)
Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC
-
Journal Title
Nat Neurosci
Volume: 14(8)
Pages: 1023-1032
Peer Reviewed
-
[Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : Evidence for γ-secretase dysfunction2011
Author(s)
Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M, Yamamoto K, Martins RN, Maeda M, Nishimura M, Levey A, Chung KA, Montine T, Leverenz J, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya N, Gandy S, Suzuki T
-
Journal Title
Ann Neurol
Volume: 69(6)
Pages: 1026-1031
Peer Reviewed
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
