Summary

We propose to study the functional consequences of a transcription factor complex that specifically forms in AD and deregulates protein expression in AD brain.Aim 1: We found that the Aß1-42-induced interaction of two transcription factors is part of AD pathology. Here, we will investigate whether the formation of this complex is sufficient to dysregulate intracellular protein trafficking, and whether as a consequence Aß1-42 production is increased. Aim 2: We propose that AD-linked transcription factor interaction dysregulates the expression of genes important for the secretion of proteins in AD brain. Here, we will investigate the consequences of neuron-specific loss of one of the transcription factors in wild type mice and in an AD mouse model.

Project Details

The search for the causes of transcriptional misregulation in disease is often aimed at finding individual transcription factors, but these proteins have important functions outside of pathology and are thus problematic as drug targets. Here, we are instead focusing on an interaction between two transcription factors in AD brain that leads to pathogenic changes in gene expression. Targeting this interaction, rather than the individual transcription factors might be a novel avenue for a disease-modifying therapy in AD. The successful completion of our research proposal will establish the concept that changes in protein expression in AD can be caused by the erroneous interaction between two transcription factors rather than by changes in their levels. We expect this principle to be apply to other diseases as well, esp. Parkinson's disease. The next step will be to investigate whether this mechanisms can be targeted therapeutically.