Room 424, Sanders-Brown Center on Aging
800 Limestone Street
Lexington, KY 40536-0230
Ph.D. University of South Florida, 2005
The role of inflammation in Alzheimer’s disease therapeutics
Our laboratory is interested in how the inflammatory response to potential therapeutics contributes the efficacy of the therapy. For instance, anti-Ab immunotherapy, which is in clinical trials for Alzheimer’s disease, significantly alters the overall inflammatory state of the brain. It is already understood that immunotherapy lowers brain levels of the major pathologies of Alzheimer’s disease and, at least in mice, improves cognition. We are interested in how the inflammatory changes contribute to the pathological changes. We are also particularly focused on the vascular adverse events that have been shown to occur due to immunotherapy. In numerous mouse studies, immunotherapy has been shown to cause microhemorrhages in the brain. Additionally, data from clinical trials would suggest that vascular adverse events also occur in humans. We have data to show that a group of proteinases linked to hemorrhage are increased as a result of immunotherapy-mediated inflammatory changes and we believe this is the cause of micorhemorrhages. We are studying whether these adverse events can be inhibited while maintaining the therapeutic efficacy of immunotherapy.
The neurovascular unit in Alzheimer’s disease pathogenesis
Another focus of our laboratory is what role the neurovascular unit plays in the progression of Alzheimer’s disease. The neurovascular unit is a term used to define the blood vessels of the brain as well as the surrounding cells that contribute to neuron-blood vessel signaling. These surrounding cells include astrocytes, neurons, microglia and pericytes. We have found that amyloid deposition in the vasculature, termed CAA, results in significant changes in the surrounding astrocytes. These changes include decreased contact with blood vessel and decreased expression of critical water and potassium channels. Overall, we believe that these changes disrupt the signaling between the astrocytes and the blood vessels resulting in a lack of neurovascular coupling, the phenomenon by which the blood vessels responds to increased neuronal activity by increasing local blood flow. Additionally, the decreased level of potassium and water channels likely contributes to disrupted potassium homeostasis, which can increase a neuron’s susceptibility to excitotoxic cell death. We are studying what effects the astrocyte changes have on the overall pathogenesis of Alzheimer’s disease, and also what the mechanism is for these changes. We hypothesize that the inflammatory response to CAA contributes significantly to the breakdown of the astrocyte network at the neurovascular unit.
Wilcock DM. The usefulness and challenges of transgenic mouse models in the study of Alzheimer's disease. CNS Neurol Disord Drug Targets. 9:386-394. 2010.
Abisambra J, Blair L, Jones J, Hill S, Kraft C, Rogers J, Koren J, Jinwal U, Lawson L, Johnson A, Jansen K, O’Leary J, Wilcock DM, Muschol M, Golde T, Weeber E, Banko J, Dickey C. Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice. J Neurosci 30:15374-15382. 2010.
Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT. Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease. Neuroscience 169:516-531. 2010.
Wilcock DM, Colton CA. Immunotherapy, vascular pathology and microhemorrhages in transgenic mice. CNS Neurol Disord Drug Targets. 8:50-64. 2009.
Wilcock DM, Vitek MP, Colton CA. Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 155:1055-1069. 2009.
Wilcock DM, Gharkhaholonarahe N, Van Nostrand WE, Davis J, Vitek MP, Colton CA. Amyloid reduction by amyloid-b vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer’s disease. J Neurosci 29:7957-7965. 2009.