DepartmentCellular and Integrative Physiology
Chu Chen, Ph.D.
B.S., Nanjing University, Nanjing, China
M.S., Zhejiang University School of Medicine, Hangzhou, China
Ph.D., Tulane University, New Orleans
Postdoctoral fellow, Louisiana State University Health Sciences Center, New Orleans
The research programs in Dr. Chen’s laboratory have been focusing on neuroinflammation in health and disease. Inflammation is now believed to be a common mechanism of disease. Neuroinflammation, the inflammatory response that occurs in the nervous system, has been implicated in many brain disorders/diseases, including epilepsy, traumatic brain injury (TBI), stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). However, our understanding of the mechanisms underlying neuroinflammation in the pathogeneses and neuropathology of neurodegenerative diseases is still limited. Importantly, there are no effective therapies currently available to prevent development of neurodegenerative diseases or to halt disease progression. To address these important issues, the current research emphasis in Dr. Chen’s laboratory is placed on exploring cellular, molecular, and epigenetic mechanisms responsible for pathogenesis and neuropathology of AD and TBI-caused chronic traumatic encephalopathy (CTE)/AD-like neuropathology and on identifying novel therapeutic targets for Alzheimer’s disease and TBI-induced neurodegenerative disease. There are several ongoing projects in Dr. Chen’s Lab at present time:
Endocannabinoid Signaling in Synaptic Function: Endocannabinoids are naturally occurring lipid signaling mediators that activate the same cannabinoid receptors as ∆9-tetrahydrocannabinol (∆9-THC), the major psychoactive ingredient in marijuana. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most studied endocannabinoids. We are particularly interested in 2-AG, which is not only the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1/2), but also functions as a retrograde messenger regulating synaptic transmission and plasticity at the both GABAergic and glutamatergic synapses. Monoacylglycerol lipase (MAGL) is the primary enzyme in the brain that hydrolyzes 85% of 2-AG to arachidonic acid, a precursor of prostaglandins and leukotrienes (See inset). Augmentation of 2-AG signaling by chronic inactivation of MAGL has been shown to alter synaptic plasticity and behavioral performance. However, the mechanism by which 2-AG regulates synaptic function is still not clear. We are exploring molecular and epigenetic mechanisms that may be important for maintaining synaptic integrity regulated by 2-AG signaling. This project is supported by the grant from NIH Mental Health Institute (R01MH113535).
Endocannabinoid Metabolism in Neurodegenerative diseases: We and others discovered previously that 2-AG exhibits profound anti-inflammatory and neuroprotective effects in response to harmful insults. Pharmacological inhibition of MAGL that boosts 2-AG signaling and reduces its metabolites (e.g., arachidonic acid and prostaglandins) reduces neuropathology and improves long-term synaptic plasticity, learning and memory in animal models of both AD and TBI. However, it is still not clear whether genetic disruption of MAGL will yield beneficial effects similar to those following pharmacological inhibition of MAGL in AD and TBI and which cell type-specific MAGL plays a role in alleviation of AD neuropathology and TBI-induced AD-like neuropathology. This study will provide important evidence supporting our idea that MAGL is a novel and promising therapeutic target for neurodegenerative diseases, including AD and TBI-induced CTE. This project is supported by the grant from NIH NINDS (R01NS076815).
Traumatic brain injury and Alzheimer’s disease: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. While the etiology of AD is multifactorial and complex, growing evidence suggests that traumatic brain injury (TBI) is a risk factor for development of AD and dementia. A single severe or repetitive mild TBI may cause CTE, the most recently defined TBI-triggered progressive neurodegenerative disease, characterized by persistent neuroinflammation, neurodegeneration, TAR DNA-binding protein 43 (TDP-43) proteinopathy, Aβ formation, hyperphosphorylated tau (p-tau), marked brain atrophy, memory loss, and dementias. We are interested in defining the mechanism that contribute to the both conditions. The results from this research project will further our understanding of the etiology and the mechanism common to both AD and TBI-induced AD-like neurodegenerative disease and ultimately identify a novel therapeutic target for preventing development of AD and/or TBI-associated AD neuropathology and dementia, or for halting disease progression. This project is supported by the grant from NIH NIA (R01AG058621).
Laboratory Manager and Senior Research Associate
Dexiao Zhu, Ph.D.
Fei Gao, Ph.D.
- Song Y, Hu M, Zhang J, Teng Z and Chen C. (2019) A novel mechanism of synaptic and cognitive impairments mediated via microRNA-30b in Alzheimer’s disease. EBioMedicine 39:409-421 PMID: 30522932 (Highlighted in this issue)
- Qian Q, Zhang J, Bao W, Zheng T, Zhou D, Zhang X, Pan H, Zhang H, He X, Sun B, Luo B, Chen C and Peng G. (2019) Downregulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer’s disease. FASEB Journal 33:4406-4417. PMID: 30576233
- Zhang J & Chen C. (2018) Alleviation of neuropathology by inhibition of monoacylglycerol lipase in APP transgenic mice lacking CB2 receptors. Molecular Neurobiology 55:4802-4810. PMID: 28733897
- Song Y, Zhang J & Chen C. (2015) Fine-tuning of synaptic upscaling at excitatory synapses by endocannabinoid signaling is mediated via the CB1 receptor. Scientific Reports 5: 16257. PMID: 26541090
- Zhang J, Teng Z, Song Y, Hu M & Chen C. (2015) Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury. Journal of Cerebral Blood Flow & Metabolism 35: 443-453. PMID: 25492114
- Xu J & Chen C. (2015) Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist 21: 152-168. PMID: 24571856
- Zhang J, Hu M, Teng Z, Tang Y & Chen C. (2014) Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer’s disease. Journal of Neuroscience 34:14919-14933. (Featured article in this issue) PMID: 25378159 Editor’s Commentary: http://www.jneurosci.org/content/34/45/i.full. Highlighted in Nature Science-Business eXchange: http://www.nature.com/scibx/journal/v7/n46/full/scibx.2014.1354.html
- Chen R, Zhang J, Fan N, Teng Z, Wu Y, Yang H, Tang Y, Sun H, Song Y & Chen C. (2013) Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154-1165. PMID: 24267894 (Featured and highlighted in Cell : http://www.elsevier.com/connect/preventing-marijuana-induced-memory-problems-with-OTC-painkillers, Science: http://news.sciencemag.org/brain-behavior/2013/11/painkillers-may-curb-memory-loss-medical-marijuana, Science Signaling: (http://stke.sciencemag.org/cgi/content/abstract/6/304/ec291), Nature: (http://www.nature.com/nature/journal/v503/n7477/full/503440b.html), Nature Reviews Neuroscience: (http://www.nature.com/nrn/journal/v15/n1/full/nrn3659.html), and covered by various news media.
- Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, Teng Z & Chen C. (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports 2:1329-1339 (Covered by various news media). PMID: 23122958
- He H, Mahnke A, Doyle S, Fan N, Wang C, Hall B, Tang YP, Inglis F, Chen C & Erickson JD (2012) Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning. Journal of Neuroscience 32:15886-15901. PMID: 23136427
- Xu J, Zhang J & Chen C. (2012) Long-lasting potentiation of hippocampal synaptic transmission by direct cortical input is mediated via endocannabinoids. Journal of Physiology (Lond) 590:2305-2315. PMID: 22411015
- Du H, Chen X, Zhang J & Chen C. (2011) Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated by PPAR-g. British Journal of Pharmacology 163:1533-1549. PMID: 21501147
- Chen X, Zhang J & Chen C. (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against b-amyloid insults. Neuroscience 178:159-168. PMID: 21256197
- Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, Carattini-Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui S-I, Nowak NJ, Roder JC, Chen C, Bradley A & Yu YE. (2010) A mouse model of Down Syndrome trisomic for all human chromosome 21 syntenic regions. Human Molecular Genetics 19:2780–2791. PMID: 20442137
- Chen C. (2010) COX-2’s new role in inflammation. Nature Chemical Biology 6: 401-402. PMID: 20479749
- Xu J, Chen R, Zhang J & Chen C. (2010) Endocannabinoids differentially modulate synaptic plasticity in rat hippocampal CA1 pyramidal neurons. PLoS ONE 5:e10306. PMID: 20421986
- Sang N, Zhang J & Chen C (2010) Anandamide potentiation of miniature spontaneous excitatory synaptic transmission is mediated via IP3 pathway. Neurochemistry International 56:590-596. PMID: 20064571
- Fan N, Yang H, Zhang J & Chen C. (2010) Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for Δ9-THC-impaired hippocampal synaptic plasticity. Journal of Neurochemistry 112:691-702. PMID: 19912468
- Yang H, Zhang J, Breyer RM & Chen C. (2009) Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor. Journal of Neurochemistry 108:295-304. PMID: 19012750
- Grewal S, Defamie N, Zhang X, Gois SD, Shawki A, Mackenzie B, Chen C, Varoqui H & Erickson JD. (2009) SNAT2 amino-acid transporter is regulated by osmolytes of the SLC6 GABA transporter subfamily and may play no role in delivering glutamine for spontaneous glutamatergic transmission. Journal of Biological Chemistry 284:11224-11236. PMID: 19240036
- Zhang J & Chen C. (2008) Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. Journal of Biological Chemistry 283: 22601–22611. PMID: 18534982
- Yang H & Chen C. (2008) COX-2 in synaptic signaling. Current Pharmaceutical Design 14: 1443-1451. PMID: 18537667
- Yang H, Zhang J, Andreasson K & Chen C. (2008) COX-2 Oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity. Molecular and Cellular Neuroscience 37: 682-695. PMID: 18295507