The Alzheimer disease (AD) brain is characterized by two types of protein aggregates, neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau, and amyloid plaques, comprised of amyloid-[unreadable] (A[unreadable]). Clinically, AD patients show a progressive deterioration of memory and other cognitive functions. Recent evidence points to soluble A[unreadable] as an excellent candidate for the initial trigger of memory loss;however, the molecular mechanisms underlying A[unreadable] -induced cognitive decline remain elusive. In our preliminary studies, we have identified the mammalian target of rapamycin (mTOR) as a potential molecular link between A[unreadable], tau and cognitive decline. Additionally, we show that A[unreadable] oligomers increase mTOR signaling, an event mediated by the [unreadable]2 adrenergic receptors ([unreadable]2ARs). To identify the mechanistic link between mTOR signaling and A[unreadable], tau and cognitive decline, three Specific Aims are proposed: Specific Aim 1 will test the hypothesis that the accumulation of A[unreadable] oligomers increases mTOR activity by a mechanism mediated by [unreadable]2ARs. mTOR plays a key role in regulating protein homeostasis;thus, unveiling the molecular pathways leading to its deregulation in AD will lead to a better understanding of the disease pathogenesis. Here we will dissect the molecular pathways that link the A[unreadable] accumulation to changes in [unreadable]2ARs/mTOR signaling. Specific Aim 2 will test the hypothesis that the A[unreadable] -induced increase in mTOR signaling further increases A[unreadable] pathology and exacerbates cognitive decline. Our preliminary data show that mTOR signaling is increased in 3xTg-AD and Tg2576 mice. Additionally, we show that reducing mTOR signaling with rapamycin, a selective mTOR inhibitor, rescues the early neuropathological and behavioral phenotypes in 6-month-old 3xTg-AD mice. Growing evidence shows that rapamycin may have mTOR-independent effects. To directly address the role of mTOR in AD, we will use a genetic approach and knockout mTOR in the brain of the Tg2576 mice. Specific Aim 3 will test the hypothesis that the increase in mTOR signaling directly contributes to the tau pathology. Our preliminary data show that restoring mTOR signaling in the 3xTg-AD mice suffices to reduce A[unreadable] and tau pathology. However, the tau pathology in these mice is highly dependent on A[unreadable] levels;therefore, it remains to be established whether the effects of restoring mTOR signaling on tau pathology are mediated by a direct interaction between mTOR and tau or are simply due to a decrease in A[unreadable] levels. Using a mouse model overexpressing wild type tau, we will use genetic and pharmacological approaches to decrease mTOR signaling and test the mechanistic link between mTOR signaling and tau pathology. Overall, the proposed Specific Aims will elucidate the underlying molecular pathways linking A[unreadable], tau and cognitive decline. The identification of the pathways that lead to cognitive decline may point to new therapeutic targets. PUBLIC HEALTH RELEVANCE: Alzheimer disease is the most common form of dementia among the elderly and the seventh leading cause of death in the United States. Our studies are aimed at understanding the molecular basis underlying memory loss and cognitive in AD decline and will facilitate the identification of potential therapeutic targets for this insidious disorder.