While the etiology of Alzheimer's disease (AD) is multifactorial and complex, results from epidemiological, clinical, and laboratory animal studies implicate traumatic brain injury (TBI) as an important risk factor for AD and dementia. However, the mechanisms by which TBI increases the risk of AD are largely unknown. In particular, there are no effective therapies to prevent or treat TBI-caused AD neuropathology and dementia. Accumulating evidence suggests that neuroinflammation following the primary injury plays a critical factor in secondary brain damage and subsequent neuropathological changes. Therefore, resolving neuroinflammation will significantly reduce secondary brain damage and eventually prevent or reduce the incidence of TBI- induced AD-like neurodegenerative disease. Endogenous cannabinoids display anti-inflammatory and neuroprotective properties. During the current period of funding, we provided evidence that monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is likely a new therapeutic target for AD. Pharmacological inactivation of MAGL reduces neuropathology and improves synaptic plasticity and memory formation in animal models of both TBI and AD. However, we do not know whether genetic disruption of MAGL will yield beneficial effects similar to those following pharmacological inhibition of MAGL in TBI. In addition, there is a gap in our knowledge about the signaling pathways that mediate anti-inflammatory and neuroprotective effects produced by MAGL inhibition in TBI. In this competing renewal application, we propose to test our hypothesis that alleviation of TBI-induced AD-like neuropathological changes by pharmacological or genetic disruption of MAGL is primarily mediated by enhancement of 2-AG signaling in astrocytes, which, in turn curbs neuroinflammation. Thus, the primary objective of the studies proposed in this application will use our established mouse model of repetitive mild closed head injury to demonstrate that inhibition of 2-AG metabolism by pharmacological inhibition or genetic disruption of MAGL ameliorates AD-like neuropathology, improves recovery of synaptic and cognitive functions, and halts disease progression and delineate the signaling pathways that mediate the beneficial effects produced by MAGL inhibition. The results from this project may ultimately lead to development of a novel therapeutic intervention for TBI-induced AD-like neurodegenerative disease.

Public Health Relevance

Accumulating evidence indicates that TBI is an important risk factor in AD development and dementia. However, there are no effective therapies available to treat or prevent TBI-associated AD neuropathology and cognitive decline. The results from the proposed studies will provide evidence that MAGL in astrocytes is a promising therapeutic target for TBI-induced AD-like neurodegenerative disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
Song, Yunping; Hu, Mei; Zhang, Jian et al. (2018) A novel mechanism of synaptic and cognitive impairments mediated via microRNA-30b in Alzheimer's disease. EBioMedicine :
Zhang, Jian; Chen, Chu (2018) Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors. Mol Neurobiol 55:4802-4810
Qian, Qi; Zhang, Jian; He, Fang-Ping et al. (2018) Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer's disease. FASEB J :fj201801846R
Chen, Chu (2016) Endocannabinoid metabolism in neurodegenerative diseases. Neuroimmunol Neuroinflamm 3:268-270
Zhang, Jian; Teng, Zhaoqian; Song, Yunping et al. (2015) Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury. J Cereb Blood Flow Metab 35:443-53
Song, Yunping; Zhang, Jian; Chen, Chu (2015) Fine-tuning of synaptic upscaling at excitatory synapses by endocannabinoid signaling is mediated via the CB1 receptor. Sci Rep 5:16257
Xu, Jian-Yi; Chen, Chu (2015) Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist 21:152-68
Chen, Chu (2015) Homeostatic regulation of brain functions by endocannabinoid signaling. Neural Regen Res 10:691-2
Zhang, Jian; Hu, Mei; Teng, Zhaoqian et al. (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. J Neurosci 34:14919-33
Chen, Rongqing; Zhang, Jian; Fan, Ni et al. (2013) ?9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154-1165

Showing the most recent 10 out of 12 publications