Does ApoE promote phagocytic degradation of amyloid-beta?
In humans, the APOE gene exists as three polymorphic alleles (ε2, ε3, and ε4). Substantial evidence confirms that APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), as APOE4 is significantly increased risk of late-onset AD, and the presence of the APOE4 allele also reduces the age of onset for AD. Studies found that reduced apoE levels in APOE4 carriers and in AD patients can promote the accumulation of Amyloid β (Aβ) in the brain, suggesting apoE may prevent Aβ accumulation.
Human apoE shows a high affinity to Aβ. The interaction between apoE and Aβ appears to depend on the isoforms and its lipidation state. The apoE4/Aβ complex is less stable compared with other isoforms. Interestingly, the APOE4 carriers and AD patients have fewer amounts of apoE/Aβ complexes in the CSF, and these patients also have higher levels of Aβ oligomers. Despite substantial evidence showing that apoE exhibits isoform-specific binding to Aβ and that apoE/Aβ complex may regulate Aβ metabolism, a 2013 study led by Holtzman’s group demonstrated that apoE has minimal interaction with Aβ in physiological conditions but that apoE promotes Aβ clearance by astrocytes via competing for low-density lipoprotein receptor-related protein 1 (LRP1).
Our research showed that one of major mechanisms of Aβ clearance in the brain is via phagocytosis by microglia. This study will try to find out whether apoE can promote the phagocytic degradation of Aβ by microglia, whether there is a difference in the potency of different isoforms, and answer how to develop a therapeutic strategy targeting Aβ phagocytic degradation with apoE for the treatment of AD.
- Produce and purify apoE3 and apoE4 proteins from stable cell lines.
- Test the effect of different apoE isoforms on phagocytic degradation of Aβ by microglia through an in vitro model.
Take part in this project
Students who are applying to study at The Florey can register their interest in this project. Refer to our step-by-step guide to help you with your application.
This project is tailored for third-year undergraduates who are interested in an internship.
If you’re interested in learning more about this project please contact our team.