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

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 Description:

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.

Selected Publications:

• Jara JH, Singh BB, Floden AM, Combs CK. Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death. J Neurochem. 2007 Mar;100(5):1407-20.
• Austin SA, Floden AM, Murphy EJ, Combs CK. Alpha-synuclein expression modulates microglial activation phenotype. J Neurosci. 2006 Oct 11;26(41):10558-63.
• Floden AM, Combs CK. 2006. Beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J Neurosci. 2006 Apr 26;26(17):4644-8.
• Sondag CM, Combs CK. 2006. Amyloid precursor protein cross-linking stimulates beta amyloid production and pro-inflammatory cytokine release in monocytic lineage cells. J Neurochem. 2006 Apr;97(2):449-61.
• Shavali S, Combs CK, Ebadi M. 2006. Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson's disease. Neurochem Res. 2006 Jan;31(1):85-94.
• Floden AM, Li S, Combs CK. 2005. Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci. 2005 Mar 9;25(10):2566-75.
• Sondag CM, Combs CK. 2004. Amyloid precursor protein mediates proinflammatory activation of monocytic lineage cells. J Biol Chem. 2004 Apr 2;279(14):14456-63.
• Combs, C K, J C Karlo, S-C Kao, G E Landreth. 2001. b-amyloid stimulation of microglia and monocytes results in TNFa-mediated neuronal apoptosis. J. Neurosci. 21(4): 1179-1188.
• Combs, C K, P Bates, J C Karlo, G E Landreth. 2001. Regulation of b-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha. Neurochem Int. 39(5-6):449-57.
• Landreth, G E, C K Combs, J Silver, M T Fitch. 2001. Compositions and methods for the treatment of Alzheimer's disease, central nervous system injury, and inflammatory diseases. U.S. Patent.
• Wu, Q, C Combs, S B Cannady, DS Geldmacher, K Herrup. 2000. Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol of Aging. 21(6): 797-806.
• Combs, C K, D E Johnson, J C Karlo, S B Cannady, G E Landreth. 2000. Inflammatory mechanisms in Alzheimer's disease: inhibition of b-amyloid stimulated proinflammatory responses and neurotoxicity by PPARg agonists. J. Neurosci. 20(2): 558-567.
• Combs, C K, D E Johnson, S B Cannady, T M Lehman, G E Landreth. 1999. Amyloidogenic fragments of the human prion and b-amyloid proteins activate a neurotoxic signaling response in microglia. J. Neurosci., 19(3):928-939.
• Fitch, M T, C Doller, C K Combs, G E Landreth, J Silver 1999. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vitro and in vivo analysis of inflammation-induced secondary injury after CNS trauma. J. Neurosci. 19(19): 8182-8198.
• McDonald, D R, Bamberger, M E, Combs, C K., G E Landreth. 1998. b-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J. Neurosci. 18 (12): 4451-4460.
• Combs, C K, P D Coleman and M K O'Banion. 1998. Developmental regulation and PKC dependence of Alzheimer-type tau phosphorylations in cultured fetal rat hippocampal neurons. Dev. Brain Res., 107: 143-158.
• J Song, C K Combs, W H Pilcher, L Y Song, A K Utal, and P D Coleman. 1997. Low initial tau phosphorylation in human brain biopsy samples. Neurobiol. Aging. 18 (5): 475-481.