Alzheimer?s disease (AD) is an aging-related neurodegenerative disorder that affects ~5.8 million people in the United States. Despite intensive research efforts in recent decades, neither an effective palliative treatment nor a cure is available, largely due to our limited understanding of the molecular mechanisms that are disrupted in this devastating disease. Current research suggests that the gradual cognitive decline in AD occurs by the concurrent deleterious action of soluble amyloid-beta (A?) oligomers (A?Os) and intracellular tau in the brain. Emerging evidence, however, suggests that development of AD may also be attributed to a progressive deterioration of mitochondrial functioning in brain cells, especially neurons. Besides, AD development has recently been linked to a progressive impairment in brain?s ability to respond to hormones such as insulin?a condition known as brain insulin resistance. To investigate these emerging but still elusive molecular mechanisms of AD, we ask the question: is there any connection between A?Os accumulation, tau, compromised mitochondrial energy metabolism, and increased insulin resistance in the AD brain and if so, how? It is known that A?Os interact with the neuronal plasma membrane, which may interrupt communications between neurons and their environment and disrupt their normal functions. We are particularly interested in how the A?Os disrupts neuron?s ability to properly respond to the presence of insulin or nutrients and how it affects ATP production and other mitochondrial functions. Along this direction, we recently discovered Nutrient-Induced Mitochondrial Activity (NiMA), a novel communication pathway between the lysosome and mitochondria, which is mediated by the lysosome-associated mechanistic target of rapamycin complex 1 (mTORC1). Interestingly, the abnormal accumulation of A?Os in AD cellular models disrupted NiMA in a tau-dependent manner. In this project, we aim to elucidate molecular mechanisms mediating NiMA and to understand how this pathway is disrupted by A?Os and tau in AD, by screening regulator of this pathway in human neurons in culture and using two-photon fluorescence lifetime imaging microscopy and state-of-the-art mitochondrial and metabolic imaging of the mouse brain in vivo. Successful completion of this project not only will advance our understanding of these earliest steps occurred in AD progression, but also may lead to new therapeutic strategies that could help us cure this disease.
Mitochondrial metabolic dysfunction has long been recognized as a key contributor to Alzheimer?s disease (AD); however, the underlying molecular mechanisms of how neurons coordinate mitochondrial activity and how they go awry in AD remain poorly understood. Combining molecular assays in mouse and human neuronal cultures and metabolic imaging in live animal brains, we seek to understand a novel mechanistic link between impaired mitochondrial metabolism, abnormal accumulation of soluble amyloid-? oligomers, Tau dysfunction and insulin resistance in AD. This effort may lead to improved understanding of AD pathogenesis and new therapeutics.