Alzheimer's disease (AD) affects 1 in 9 people over the age of 65 in the U.S. and is the 6th leading cause of death in the US. There is no effective treatment for AD. While the number of people affected by AD is expected to rise rapidly with the increasing age of the U.S. population, our nation's Veteran population is at an even greater risk for developing AD because of the recent increase in combat-related injuries such as traumatic brain injury and posttraumatic stress disorder, both of which are significant risk factors for AD. Recent studies from our and others' laboratories showed that attenuation of the mechanistic target of rapamycin (mTOR) with rapamycin halts the progression of AD-like memory deficits in several different mouse models of AD even when treatment is started after the onset of AD-like cognitive deficits, effectively `stopping' the progression of the disease until the end of lifespan. Systemic rapamycin ameliorates learning and memory deficits, decreases brain amyloid ? levels by increasing autophagy, and restores brain vascular function and integrity in AD mice. The specific contribution of neuronal versus vascular mechanisms in the restoration of memory in AD mice by attenuation of mTORC1, the main target of rapamycin, however, is still unknown. The present research proposal will define the contribution of neuron-driven mTORC1-dependent mechanisms to the pathogenesis of AD by genetically knocking down mTORC1 specifically in neurons of adult AD-model mice. The proposed research is innovative because it focuses on the contribution of mTORC1-driven mechanisms acting specifically in neurons, that will be examined using a uniquely novel neuronal-specific adult mTORC1 knockdown mouse model of AD; and is significant, as it will lead to a better understanding of AD pathogenesis and will identify novel targets for clinical interventions. With the aims of this proposal, I will test the hypothesis that reducing mTORC1 specifically in neurons will ameliorate AD-like cognitive deficits in AD mice (Aim 1) by increasing autophagy at the synapse and improving synaptic function (Aim 2), and by improving brain vascular health (Aim 3). If my studies support this hypothesis, my work is expected to have a positive impact on Veteran's health because it will lead to the development of targeted pharmacological strategies to treat AD, including but not limited to drugs that are currently FDA-approved for clinical use. Thus my findings could be rapidly translated to treatments for AD. In addition, my studies will reveal the mechanisms by which attenuating mTORC1 in neurons contributes to halting the progression of AD-like disease in mice, and thus will significantly advance our understanding of the pathogenesis of AD. By performing the proposed research, I will obtain training in key experimental approaches as well as gain critical experience in various aspects of professional development. This training will significantly advance my research career goals and will enable me to become a competitive independent VA research investigator focused on improving the health of Veterans suffering from AD.
Our and other's recent studies demonstrated that systemic pharmacological attenuation of the mechanistic target of rapamycin (mTOR) halts and even reverses Alzheimer's (AD)-like memory deficits, restores cerebral blood flow, decreases amyloid, and restores vascular reactivity in brains of several different models of AD. How and to what extent neuronal versus vascular mechanisms contribute to the amelioration of AD-like deficits in AD mice treated with rapamycin is still unknown. The present proposal will define how neuronal mTORC1-driven mechanisms contribute to the pathogenesis of AD using a uniquely novel neuronal-specific adult mTORC1 knockdown mouse model of AD. My work is expected to have a positive impact on Veteran's health because it will identify neuron-specific mTORC1-dependent mechanisms of AD, and thus will advance our understanding of AD and lead to the development of targeted pharmacological strategies to treat AD, including but not limited to drugs that are currently FDA-approved for clinical use.