Colin K. Combs, PhD

Education/Training:

• Postdoctoral Fellow, Case Western Reserve University, School of Medicine, Cleveland, OH
• Ph.D., University of Rochester, School of Medicine and Dentistry, Rochester, NY
• B.A. Berea College, Berea, KY

Research Activity:

One of our research goals is to determine the mechanisms by which inflammatory activation of brain glial cells contributes to neurodegeneration. Currently, our main interest is the process by which a specific type of glia, microglia, contribute to the pathophysiology of Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by progressive dementia and an accumulation of extracellular senile plaques and intracellular neurofibrillary tangles in the brain. In addition, diseased brains exhibit a profoundly increased microglial and astrocyte activation phenotype. One prevailing theory is that this “gliosis” contributes to the neuron loss that is observed during disease.

Microglia are the resident immune effector cells of the brain and their activation state can likely contribute to both degeneration and regeneration. This dichotomy provides the opportunity to modulate their phenotype to promote their regenerative function while limiting their degenerative behavior. For example, it is now becoming clearer that many of the neurodegenerative diseases that afflict our brains result, in part, from aberrant microglial responses. In addition to AD, Parkinson’s disease, amyotropic lateral sclerosis, and multiple sclerosis are other examples of chronic nervous system diseases in which microglial hyper-reactivity likely contributes to the cell death that occurs. We are working to understand specifically what goes wrong with the microglia in these conditions. Once we identify the nature of the pathologic response, we work to stop or reverse it in an effort to promote cell survival in the brain. This approach allows us to identify and propose novel therapeutic agents for treating these diseases. We routinely use in vitro primary cell culture models of disease to first define our molecular targets for therapeutic intervention. Next, we verify the efficacy of our approach through in vivo whole animal rodent models of disease. Currently we are pursuing ongoing projects related to Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, and multiple sclerosis.

Keywords:

neurodegeneration, Alzheimer's disease,neuroinflammation, cytokines, TNFa,apoptosis, signal transduction, kinases, microglia, astrocytes, excitotoxicity, b-amyloid, tau, amyloid plaques, neurofibrillary tangles, glutamate, cyclooxygenase-2, nitric oxide, superoxide anion, nitric oxide synthase, tyrosine kinases, serine/threonine kinases, PPARg

Selected Publications:

• Puig KL, Floden AM, Adhikari R, Golovko MY, Combs CK. (2012) Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One 7(1):e30378.
• Dhawan G, Floden AM, Combs CK (2011) Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging. Nov 29. [Epub ahead of print].
• Puig KL, Swigost AJ, Zhou X, Sens MA, Combs CK. (2011) Amyloid precursor protein expression modulates intestine immune phenotype. J Neuroimmune Pharmacol. Nov 29. [Epub ahead of print]. Invited article.
• Rojanathammanee, L., Murphy, E.J., and Combs, C.K. (2011) Expression of mutant alpha-synuclein modulates microglial phenotype in vitro. J. Neuroinflammation 8:44.
• Grisanti LA, Woster AP, Dahlman J, Sauter ER, Combs CK, Porter JE. {alpha}1-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages. J Pharmacol Exp Ther. 2011 Aug;338(2):648-57. Epub 2011 May 13.
• Floden AM and Combs CK (2011). Microglia Demonstrate Age-Dependent Interaction with Beta-amyloid Fibrils J. Alz. Disease 25(2):279-93.
• Austin SA, Rojanathammanee L, Golovko MY, Murphy EJ and Combs, CK (2011) Lack of alpha-synuclein modulates microglial phenotype in vitro. Neurochem Res 36(6):994-1004.
• Nagamoto-Combs K and Combs CK (2010) Microglial phenotype is regulated by activity of the transcription factor, NFAT (nuclear factor of activated T cells). J. Neuroscience. 30:9641-9646.
• Sondag, CM and Combs, CK (2010) Adhesion of monocytes to type I collagen stimulates an APP-dependent proinflammatory signaling response and release of Aβ1-40. J. Neuroinflammation. 7:22.
• Nagamoto-Combs K, Morecraft RJ, Darling WG, Combs C. (2010) Long-Term Gliosis and Molecular Changes in the Cervical Spinal Cord of the Rhesus Monkey after Traumatic Brain Injury. J Neurotrauma. 27:565-585.
• Grisanti LA, Evanson J, Jorissen H, Woster AP, Combs CK and Porter JE (2010) Pro-Inflammatory Responses in Human Monocytes are β1-adrenergic Receptor Subtype Dependent. Mol Immunol. 47:1244-1254.
• Austin, SA and Combs, CK. (2010) Amyloid precursor protein mediates monocyte adhesion to AD tissue and ApoE-/- mice. Neurobiol Aging. 31:1854-1866. Epub 2008 Dec 5.
• Austin, SA, Sens, MA, Combs, CK (2009) Amyloid Precursor Protein Mediates a Tyrosine-kinase Dependent Activation Response in Endothelial Cells. J. Neurosci. 29:14451-14462
• Sondag CM, Dhawan, G, and Combs, CK. (2009) Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation. 6:1.
• Golovko MY, Barceló-Coblijn G, Castagnet PI, Austin S, Combs CK, Murphy EJ. (2009) The role of alpha-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response. Mol Cell Biochem. 326:55-66.
• Nagamoto-Combs, K, McNeal DW, Morecraft RJ, Combs CK. 2007. Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury. J Neurotrauma.24:1719-1742.
• Woster, AW, Combs, CK. 2007. Differential ability of a thiazolidinedione PPARγ agonist to attenuate cytokine secretion in primary microglia and macrophage-like cells. J. Neurochem. 103:67-76.
• Floden, AM, and Combs, CK. 2007. Microglia repetitively isolated from in vitro mixed glial cultures retain their initial phenotype. J. Neurosci Methods. 164:218-224.
• Jara, JH, Singh, BB, Floden, AM, and Combs, CK. 2007. Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death. J Neurochem. 100:1407-1420.