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-ß 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.