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発表内容

Title:
APP/TAG-1 negatively modulates neurogenesis via Fe65.

Name & Affiliation:
Yasuo Takeda, Ph.D.
Professor and Director, Department of Clinical Pharmacy and Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences.

Abstract:
Amyloid precursor protein (APP) plays a central role in the pathogenesis of the neurodegenerative disorder, Alzheimer’s disease. APP is a type I transmembrane protein with a large extracellular domain, a single transmembrane region and a short cytoplasmic domain. The regulated intramembrane proteolysis (RIP) processing of APP is strikingly similar to that of the Notch receptor. The release of APP intracellular domain (AICD) may be triggered by extracellular cues through γ-secretase-dependent cleavage . Here, we discovered TAG-1, a member of F3/contactin subgroup of immunoglobulin superfamipy, as a functional ligand of APP.
We have shown that both APP and TAG-1 colocalize in neural stem cells in niche area of subventricular zone (SVZ). In the case of using neuronal precursor cells (NPCs) isolated from either APP -/- , TAG-1 -/- or double knockout mice , their neurogenesis are significantly promoted compared to that of wild type. Thus, the results describe that a TAG-1/APP signaling pathway negatively modulates neurogenesis in the embryonic stage. TAG-1 increased AICD release triggered in a γ-secretase-dependent manner. We also identified Fe65, adaptor protein, which was expressed in the SVZ and NPCs, as a binding partner of AICD and found it inhibiting neurogenesis. These results indicate that a TAG-1/APP signalling pathway negatively modulates neurogenesis through Fe65.
In this seminar, a possible contribution of AICD to Alzheimer’s disease will be also discussed.

References:
1. Ebinu, J.O. and Yankner, B.A., A RIP tide in neuronal signal transduction., Neuron, 34: 499-502, 2002.

2. Ma, Q.H. at al., A TAG1-APP signaling pathway through Fe65 negatively modulates neurogenesis. Nature Cell Biol., 10: 283-294, 2008.

3. Beckett, C. et al., Nuclear signaling by membrane protein intracellular domains: the AICD enigma., Cellular Signaling, 24: 402-409, 2012.