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 Dr. Veronica Galvan's 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 our 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 AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M,
Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter
JD, Fox PT, Galvan V. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab. 2013 Sep;33(9):1412-21.
Lin AL, Pulliam DA, Deepa SS, Halloran JJ, Hussong SA, Burbank RR,
Bresnen A, Liu Y, Podlutskaya N, Soundararajan A, Muir E, Duong TQ,
Bokov AF, Viscomi C, Zeviani M, Richardson AG, Van Remmen H, Fox PT,
Galvan V. Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice. J Cereb Blood Flow Metab. 2013 Oct;33(10):1605-11.
Pierce A, Podlutskaya N, Halloran JJ, Hussong SA, Lin PY, Burbank R, Hart MJ, Galvan V. 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. 2013 Mar;124(6):880-93.
Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice.. Neuroscience. 2012 Oct 25;223:102-13.
Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010 Apr 1;5(4):e9979.