Transcriptional Mechanisms of Memory Loss in Alzheimer´s Disease
Alterations in gene expression in the brain are associated with cognitive decline in normal and pathological aging, suggesting that deregulation of gene expression may underlie synaptic and memory dysfunction in memory disorders. The goal of this project is to investigate novel molecular mechanisms that regulate gene expression programs causing memory impairments at early Alzheimer´s disease stages. In this project, we will examine the role of the transcriptional co-activator Crtc1 on memory processing and Alzheimer´s disease pathogenesis in novel Crtc1 mutant mice. We will also assay novel Crtc1 activating approaches to treat pathological and memory changes in Alzheimer´s disease mouse models.
Alzheimer´s disease is a neurodegenerative disorder characterized by cognitive impairment at early disease stages, but the cellular events that cause brain dysfunction and memory impairment at early disease stages are largely unknown. Recent studies from our lab suggest that the Creb regulated transcription coactivator-1 (Crtc1) regulates genes essential for learning and memory, whereas Crtc1 dysfunction is evident at early Alzheimer´s disease stages. In this project, we will investigate the role of Crtc1 on synaptic and memory dysfunction and pathological changes associated with Alzheimer´s disease. To discern the biological function of Crtc1 in the brain, we will first use pioneering approaches to generate and characterize novel mutant Crtc1 mouse models. Second, we will study the role of Crtc1 on Alzheimer´s-associated pathology and memory by manipulating Crtc1 function in the brain of Alzheimer´s disease transgenic mice. Finally, we will assay novel Crtc1 gene therapy approaches to ameliorate or reverse memory loss in Alzheimer´s disease transgenic mice. If successful, this project will provide knowledge of novel molecular targets and new therapeutic strategies for early treatment of Alzheimer´s disease and related neurological disorders. Specifically, the results of this project will provide clues for targeting brain transcriptome to treat memory loss in Alzheimer´s disease.