A disease-specific transcription factor complex regulates endosomal trafficking in Alzheimer´s Disease
Columbia University Medical Center (NY, USA)
Endosomal trafficking has emerged in genetic and functional studies as a pathogenic hub in Alzheimer's disease (AD). Numerous AD-linked mutations have been identified in key components of the molecular machineries regulation endosomal trafficking, and the expression levels of these proteins are changed in late onset AD. Currently, there is little information about the transcriptional control of endosomal trafficking and how it might be disrupted in AD. We identified two transcription factors whose synthesis is specifically induced in response to oligomeric Abeta. The coordinated synthesis of these transcription factors leads to their complex formation which otherwise is stoichiometrically disfavored. Using patient post-mortem tissue, we found this unusual transcription factor complex in AD but not age-matched control brains. By chromatin immunoprecipition from patient tissue, we established the gene targets of this transcription factor complex leading to its identification as a master regulator of endosomal trafficking-related genes. In summary, we found a molecular pathway linking amyloid pathology to disruption in vesicle trafficking. Inhibition of this pathway might be a novel avenue for the development of a disease-modifying therapy for AD.
Host: Jimena Baleriola