NCBI Public URL (Full List of Publications with PubMed Links)
I. Microglia & Progressive Neurotoxicity
Chronic microglial activation is implicated in the progressive nature of the neuronal loss in CNS diseases/damage. Why the microglial response is chronic and when it culminates in neuron damage is poorly understood. Over the years, our work has centered on identifying instigating triggers of deleterious activation (ex. neuron injury, LPS, and air pollution), establishing appropriate in vitro/in vivo models for studying chronic effects, and revealing the molecular mechanisms driving the persistent microglial response culminating in neurotoxicity.
1.) Levesque S, Wilson B, Gregoria V, Thorpe LB, Dallas S, Polikov VS, Hong JS, Block ML. Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity. Brain 2010 Mar;133(Pt 3):808-21. PMCID: PMC286070
2.) Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007 Apr 1;55(5):453-62. PMCID: PMC2871685
3.) Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007 Jan;8(1):57-69.
4.) Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 2005 Jun;76(2):77-98.
II. The Impact of Air Pollution on Microglia-mediated Neuropathology & Disease
Increasing reports implicate air pollution in deleterious CNS health effects (including increased AD risk), but the mechanisms driving these phenomena are largely unknown. Our previous mechanistic work has focused on how particulate matter (the particle components of urban air pollution) can activate microglia to instigate neuroinflammation and impact neurodegenerative disease pathways/cause neuron damage. Our current work indicates that lung damage itself may activate microglia to impact CNS health.
5.) Mumaw CL, Levesque S, McGraw C, Robertson S, Lucas S, Stafflinger JE, Campen MJ, Hall P, Norenberg JP, Anderson T, Lund AK, McDonald JD, Ottens AK, Block ML. Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors. FASEB J 2016 Feb 10. PMCID: in progress.
6.) Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A, Johnson JA, Duke L, Kodavanti P, Surace MJ, Block ML. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ Health Perspect 2011 Aug;119(8):1149-55. PMCID: PMC3237351
7.) Levesque S, Surace MJ, McDonald J, Block ML. Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation 2011;8:105. PMCID: PMC3184279
8.) Block ML, Calderon-Garciduenas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci 2009 Sep;32(9):506-16. PMCID: PMC318427
III. Reactive Oxygen Species in Microglia Pathology & Microglia-mediated Neurotoxicity
The bulk of our previous work has emphasized that reactive oxygen species (ROS) are key mediators of microglia-mediated neurotoxicity. However, the precise mechanisms through which ROS reprogram microglia to become a neurotoxic phenotype are unknown. Over the years, we have identified numerous triggers (environmental compounds and endogenous disease processes) of microglial ROS production and associated neurotoxicity. Recently, we have begun to explore the redox signaling driving microglial priming responsible for the chronically M1 activated microglia phenotype.
9.) Taetzsch T, Levesque S, McGraw C, Brookins S, Luqa R, Bonini MG, Mason RP, Oh U, Block ML Redox regulation of NF-kappaB p50 and M1 polarization in microglia. 2015. Glia. doi:10.1002/glia.2276. PMCID: in progress
10.) Pei Z, Pang H, Qian L, Yang S, Wang T, Zhang W, Wu X, Dallas S, Wilson B, Reece JM, Miller DS, Hong JS, Block ML. MAC1 mediates LPS-induced production of superoxide by microglia: the role of pattern recognition receptors in dopaminergic neurotoxicity. Glia 2007 Oct;55(13):1362-73.
11.) Block ML, Li G, Qin L, Wu X, Pei Z, Wang T, Wilson B, Yang J, Hong JS. Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin. FASEB J 2006 Feb;20(2):251-8.
12.) Block ML, Wu X, Pei Z, Li G, Wang T, Qin L, Wilson B, Yang J, Hong JS, Veronesi B. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J 2004 Oct;18(13):1618-20.
IV. Neuroprotection Through Microglial Inhibition
Given the critical role of microglial ROS in chronic neurotoxicity, our research strives to use our acquired mechanistic information to identify potential therapeutic targets. In addition to being a co-inventor on a patent for compounds targeting microglial ROS, my research program frequently explores novel approaches to controlling microglial activation in an effort to halt chronic neuron damage in several neurodegenerative disease models.
13.) Block ML. Neuroinflammation: Modulating mighty microglia. Nature Chemical Biology. 2014. 10 (12):988-989. doi:10.1038/nchembio.169. PMCID: in progress
14.) Lull ME, Levesque S, Surace MJ, Block ML. Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice. PLoS One 2011;6(5):e20153. PMCID: PMC31050
15.) Ding Y, Qiao A, Wang Z, Goodwin JS, Lee ES, Block ML, Allsbrook M, McDonald MP, Fan GH. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J Neurosci 2008 Nov 5;28(45):11622-34. PMCID: PMC3844785
16.) Block ML. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 2008;9 Suppl 2:S8. PMCID: PMC2604892