Aging is the primary risk factor for Alzheimer's disease (AD) and related disorders. Nevertheless, the mechanisms by which aging contributes to the onset of the disease remain elusive. In this application, we will attempt to identify critical signaling pathways that might link aging to AD pathogenesis. We focus on the ribosomal protein S6 kinase 1 (S6K1), a ubiquitously expressed protein with an established link to aging. For example, genetic deletion of the S6K1 gene in mice increases lifespan and decreases the incident of age- dependent motor dysfunction, insulin sensitivity, and obesity. A large body of evidence also points to S6K1 as playing a pivotal role in regulating astrocyte function during physiological and pathological conditions. For instance, reduction of S6K1 signaling reduces secretion of pro-inflammatory cytokines in activated astrocytes. We and others have shown that S6K1 activity is increased in postmortem human AD brains. In addition, we show that genetic reduction of S6K1 ameliorates amyloid-? and tau pathology and improves synaptic function and cognition in 3xTg-AD mice, a widely used animal model of AD. Mechanistically, we identified the Retinoblastoma- Binding Protein 7 (Rbbp7), a chromatin remodeling factor, as a possible link between S6K1 and tau. These novel and exciting findings led us to the following hypothesis: S6K1 represents a link between aging and AD.
Specific Aim 1 will identify the relative contribution of astrocytic and neuronal S6K1 hyperactivity in AD. These experiments will lead to a better understanding of how S6K1 modulates cognition and neurodegeneration in AD. Given the role of S6K1 in aging, this research is a critical step toward unveiling the mechanisms linking aging and AD.
Specific Aim 2 will identify the mechanistic link between S6K1 and AD. These experiments will elucidate the signaling pathways linking S6K1 to AD pathogenesis. In addition, if successful, the results obtained here will corroborate Rbbp7 as a novel molecular target for AD and other tauopathies.
Specific Aim 3 will identify the role of S6K1 in the gene expression dysregulation observed in AD. The results of this Aim will provide a detailed S6K1 gene regulatory network in the context of aging and AD and identify an S6K1-mediated gene expression signature that is unique between aging and AD. Impact: This application will define the mechanistic links between S6K1 and AD. Furthermore, given the role of S6K1 signaling in aging, our results may unveil new mechanisms by which aging contributes to the development of AD. Elucidating these mechanisms will likely identify several novel putative therapeutic targets for AD.
Alzheimer's disease is the most common form of dementia among the elderly and the sixth leading cause of death in the United States. This application aims at identifying the key molecular events linked aging, the major risk factor for AD, and disease etiology. Elucidating these mechanisms will likely highlight several novel and clinically translatable targets; thus, aiding in the development of new treatment for AD.
