Aging is the greatest known risk factor for Alzheimer's disease. Very little is known, however, about the molecular mechanisms that link the regulation of brain aging to diseases like Alzheimer's. The broad goal of my research group is to identify molecular pathways that make the aged brain vulnerable to Alzheimer's, and potentially to other neurodegenerations.
Our hypothesis is that these pathways can be harnessed to delay, treat or prevent Alzheimer's, and we have identified the target-of-rapamycin (TOR), a major regulator of metabolism and organismal aging, as a central driver of AD pathogenesis.
In addition to genetic experiments in mouse models, we test potential drug candidate molecules with neurobehavioral, in vivo brain optical and functional imaging, as well as cellular and molecular biology tools to determine the effect of these interventions on cognitive outcomes, and to define the mechanisms involved.
We have demonstrated key roles of TOR in the maintenance of neuronal and brain vascular function. Because TOR controls key aspects of metabolism in most cell types we hypothesize that TOR may be involved in several cell- and tissue-specific complex disease mechanisms driving neurodegeneration in AD. Thus, to define the role of TOR in AD, we study mechanisms by which pathways centered on TOR but mediating distinct processes in different brain compartments such as neurons and brain vasculature synergize to precipitate loss of function.
Other interests of my research group are (1) to determine the role of TOR signaling from neurons in the control of organismal aging in mammals, and (2) to investigate the potential of modulating adult neurogenesis or using neuronal precursor cells generated in vitro for treating neurodegeneration.
Lin A, Halloran JJ, Burbank RR, Korde S, Zheng W, Hussong SA, Podlutskaya N, Strong R, Richardson A, Hart MJ, Fox PT, Lechleiter J, Galvan V (2013). Chronic rapamycin restores brain vascular density and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab. Jun 26. PMID: 23801246.
Lin A, Pulliam D, Sathyaseelan D, Halloran JJ, Burbank RR, Hussong SA, Bresnen A, Soundararajan A, Muir E, Duong TQ, Viscomi C, Zeviani M, Richardson AG, Van Remmen H, Fox PT, Galvan V (2013)Decreased in vitro Mitochondrial Function is Associated With Enhanced Brain Metabolism, Blood Flow, and Memory in Surf1 Deficient Mice. J Cereb Blood Flow Metab. Jul 10. PMID: 23838831.
Pierce A, Podlutskaya NP, Halloran JJ, Hussong SA, Lin PY, Burbank R, Strong R, Richardson R, Hart MJ and Galvan V (2013).Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer's-like deficits in mice modeling the disease. J Neurochem. 194:880-893.
Halloran JJ, Hussong S, Podlutskaya N, Burbank R, Austad S, Hart MJ, Fischer K and Galvan V. (2012) Long-term mTOR inhibition by rapamycin modulates cognitive and non-cognitive components of behavior in mice. Neurosci. 223:102-113.
Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R and Galvan V (2010)Rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 5:e9979.