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Aβ modulates actin cytoskeleton via SHIP2-mediated phosphoinositide metabolism
Hae Nim Lee1, Kyoung Mi Sim1,2, Hyunbin Kim1,3
1Convergence Research Center for Diagnosis Treatment Care of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
Scientific Reports
|October 31, 2019
Summary
Alzheimer's disease (AD) involves altered phospholipid metabolism. Amyloid-beta (Aβ) activates SHIP2, increasing PI(3,4)P2, degrading ARAP3, and causing actin disruption, a novel AD pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Phospholipid metabolism is dysregulated in Alzheimer's disease (AD), but mechanisms remain unclear.
- Amyloid-beta (Aβ) peptides directly enhance the activity of the phosphoinositide-metabolizing enzyme SHIP2.
Purpose of the Study:
- To elucidate the molecular mechanisms linking Aβ, phospholipid metabolism, and neurodegeneration in AD.
- To investigate the role of SHIP2 and its downstream effectors in Aβ-induced cellular changes.
Main Methods:
- Utilized a fluorescent SHIP2 biosensor to monitor PI(3,4)P2 vesicle dynamics in Aβ-treated HT22 cells.
- Investigated the interaction of ARAP3 with PI(3,4)P2-positive endosomes.
- Assessed the impact of ARAP3 degradation on RhoA activity and actin polymerization.
Main Results:
- Aβ treatment led to a real-time increase of PI(3,4)P2-containing vesicles, accumulating in late endosomes and lysosomes.
- ARAP3 was recruited to PI(3,4)P2-positive endosomes via its PH domain, facilitating its degradation.
- Reduced ARAP3 levels resulted in RhoA hyperactivation and filamentous actin formation, key features of AD neurodegeneration.
Conclusions:
- Identified a novel molecular pathway: SHIP2-PI(3,4)P2-ARAP3-RhoA, linking Aβ to actin disruption via aberrant phosphoinositide metabolism.
- This pathway represents a potential therapeutic target for synaptic dysfunction in Alzheimer's disease.
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