Targeting the Endosome for Alzheimer's Drug Discovery
Apolipoprotein E4 (ApoE4) status is the primary and biomedically most important risk factor for Alzheimer’s disease (AD). We have found a novel mechanism by which ApoE4 weakens synaptic strength in neurons, which led us to identify a promising novel endosomal drug target. This proposal aims to establish the necessary mechanistic and infrastructural baseline to screen for modifiers of endosomal function and for discovering novel potential methods to target the endosome in vitro and in vivo. This is necessary for the evolution of a conceptually novel and therapeutically effective preventive approach to AD, at least for the majority of patients carrying the ApoE4 allele.
Apolipoprotein E4 status is the primary and biomedically most important risk factor for Alzheimer’s disease. We have found that upon internalization by neurons, ApoE4 leads to an endosomal vesicular trafficking defect that sequesters ApoE receptors and neurotransmitter receptors in the endosome, thereby weakening synaptic strength. Based on available structural and functional data, we predicted and experimentally demonstrated that it is possible to modify ApoE structure as well as endosomal function to restore normal ApoE recycling, revealing this approach as a promising novel drug target.
Thus, this project investigates the endosome as a novel and largely unexplored target for drug development. We have presented ample experimental evidence for the validity of the target and the feasibility of developing drugs targeting this endosomal protein. Successful completion of the project would establish a novel therapeutic approach to AD that has the potential to abolish the ApoE4 risk for developing the most frequent late-onset form of the disease.