Background: The rise of Alzheimer’s disease (AD) in an aging population presents the need for research to find novel targets for therapeutic intervention. The current mortality rate illustrates the deficit in pharmaceutical prevention or treatment for AD. The hallmarks of AD involve the development of neurofibrillary tangles (NFTs) initiating from the hyper-phosphorylation of tau. Therefore the neurodegenerative process is centrally involved with the NFTs inducing neurodegeneration leading to the continuation of AD. Neuronal spine stability is compromised during Tau phosphorylation, NFT formation and the neurodegenerative process. RanBP9 is the scaffolding protein responsible for stabilizing the protein-protein interaction between cofilin and SSH1 to facilitate the activation of cofilin.

            We are developing novel RanBP9 inhibitors to prevent the interaction between cofilin and SSH1. Within RanBP9, the SPRY domain is the location where SSH1 and cofilin dock to dephosphorylate the cofilin whereas the LisH domain is involved in actin binding. Thus we have developed novel compounds in-silico for RanBP9 that interacts with the SPRY and LisH domains to prevent the interactions between SSH1 and cofilin. Targeting overactive cofilin is a crucial component for improving actin dynamics and spine stability.

Methods: We will use primary cortex and hippocampal neurons to determine the impact of compound 9 on cofilin activation.  Second confocal laser microscopy will help define spine density, spine length and overall spine shape. Western analysis will determine the activity (phosphorylation) of Cofilin and SSH1.

Results: Our data is preliminary however our in-silico analysis has determined that compound 9 may serve as a potential RanBP9 inhibitor and thus prevent cofilin activation and spine degradation.

Conclusions: Compound 9 forms interactions with the SPRY domain resulting in preventing SSH1 interacting with cofilin for its activation. Future work will focus upon developing compounds for the LisH domain which forms interactions with Tau and Actin.