mTOR at the crossroad between aging and Alzheimer's disease

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Abstract 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 mammalian target of rapamycin (mTOR), a ubiquitously expressed protein with an established link to aging. For example, reduction of mTOR signaling in mice extends lifespan and improves age-dependent motor dysfunction, insulin sensitivity, obesity, and immune system function. A large body of evidence also points to mTOR as playing a pivotal role in regulating microglia function during physiological and pathological conditions. For instance, reducing mTOR signaling in microglia reduces secretion of pro-inflammatory cytokines, reactive oxygen species, and other toxic compounds from activated microglia. We and others have shown that mTOR signaling is increased in postmortem human AD brains. In addition, we show that genetic and pharmacological reduction of mTOR ameliorates amyloid-β and tau pathology, and improves synaptic function and cognition in multiple animal models AD. Mechanistically, we identified the Solute Carrier Family 8 Member 2 (SLC8A2), a neuronal Na+/Ca2+ pump, as a possible link between mTOR and AD. These novel and exciting findings led us to the following hypothesis: mTOR represents a link between aging and AD. Specific Aim 1 will identify the role of microglial mTOR hyperactivity in AD. These experiments will lead to a better understanding of how mTOR modulates cognition and neurodegeneration in AD. Given the role of mTOR in aging, this aim is a critical step toward unveiling the mechanisms linking aging and AD. Specific Aim 2 will elucidate the signaling pathways linking mTOR to AD pathogenesis. In addition, if successful, the results of this aim will corroborate SLC8A2 as a novel molecular target for AD and related disorders. Specific Aim 3 will identify the role of mTOR in the gene expression dysregulation observed in AD. The results of this Aim will provide a detailed mTOR gene regulatory network in the context of aging and AD and identify an mTOR-mediated gene expression signature that is unique between aging and AD. Impact: This application will define the mechanistic links between mTOR and AD. Furthermore, given the role of mTOR 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.