In Alzheimer’s disease, axons are frequently the first part of a neuron to be affected. Neurodegenerative stimuli trigger local signaling pathways that cause the retrograde spread of disease. We have found that application of beta-amyloid within minutes triggers the intra-axonal synthesis of proteins that form a unique transcription factor complex. The formation and function of this complex is required for the induction of neurodegeneration in response to the AD-related peptide oligomeric Aβ1-42. The appearance of this transcription factor complex in human postmortem brain tissue is restricted to AD brains. Here, we propose that the presence of this transcription factor complex in the central nervous system is a hallmark of age-related neurodegenerative disorders, including Alzheimer’s disease. With the experiments in this proposal we will investigate the relevance of the disease-specific transcription factor complex for the various pathological manifestations of Alzheimer’s disease, and we will study which genes are up- or downregulated by it. We will contrast these results from Alzheimer’s disease brain with findings in Parkinson’s disease brain, to determine how signaling via the complex differs in distinct neurodegenerative disorders. Using genetic and pharmacological approaches, we will investigate in mouse models of Alzheimer’s disease, whether interference with the disease-specific transcription factor complex slows down or prevents disease progression. Together, the results from this research project will establish a novel mechanism by which neurons react to oligomeric Aβ1-42. Our results will provide the rationale for targeting this signaling mechanism and test the feasibility of such an approach.