121st General Meeting of the KCS

Type Poster Presentation
Area Life Chemistry
Room No. Event Hall
Time 4월 20일 (금요일) 11:00~12:30
Code BIO.P-283
Subject The β-amyloid protein increases RhoA activity by SHIP2-mediated reduction of ARAP3 level
Authors Haenim Lee, Jeongmin Ju, Ae Nim Pae, Jihye Seong*
Convergence Research Center for Diagnosis Treatment Care of Dememtia, Korea Institute of Science and Technology, Korea
Abstract The Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with increased levels of aggregated β-amyloid protein (Aβ) in the brain. Recently, it has been shown that Aβ induces tau pathology through the activation of Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) [1]. While tau is crucial for microtubule stability and thus axonal structure in neurons, another important cytoskeleton actin is also important for neurite dynamics and synaptic connections. Thus, we further investigated the role of Aβ-induced SHIP2 activation in actin-related pathological pathways in AD. SHIP2 is an inositol phosphatase, which dephosphorylates PI(3,4,5)P3 to PI(3,4)P2. To explore the SHIP2 activity in live cells, we generated a fluorescent sensor containing the PH domain of TAPP1 that specifically binds to PI(3,4)P2. Utilizing this sensor, we found that Aβ increases the SHIP2-mediated production of PI(3,4)P2, in particular at the endosome structures. It has been previously suggested that SHIP2 directly interacts with ARAP3, a negative regulator for RhoA [2]. Thus we next check the distribution and expression of ARAP3, and interestingly ARAP3 level was reduced in response to Aβ. And as a result, the RhoA was hyper-activated when detected by the RhoA biosensor based on FRET. As RhoA is a crucial regulator for actin dynamics and neurite retraction, this SHIP2-ARAP3-RhoA signaling pathway can explain the synaptic dysfunctions in AD. We are currently further investigating whether SHIP2-induced endocytosis and degradation process are directly involved in the decreased level of ARAP3 and the subsequent increase of RhoA activity. These results will explain the Aβ-induced pathological mechanisms of neurite retraction and synaptic dysfunctions in AD.
E-mail lhn2726@naver.com