Discipline: Biological Sciences
Subcategory: Physiology and Health
Kamal Tusa - University of Minnesota
Co-Author(s): Cayla M. Duffy, Vijayakumar Marvanji, and Joshua P. Nixon, Veterans Health System, Minneapolis, MN Tammy A. Butterick, Veterans Health System, Minneapolis, MN and Minnesota Obesity Center, St. Paul Minnesota
Obesity increases the risk of Alzheimer’s disease (AD) and cognitive decline. Neuroinflammation, accompanied with a progressive neuronal loss, is known to be heightened in cognitive decline and obesity. The risk of neuroinflammation and cognitive impairment is aggravated by chronic consumption of high fat diets (HFD) rich in saturated fatty acids such palmitic acid (PA). Palmitic acid can directly stimulate microglial (brain immune cells) and increase pro-inflammatory cytokines. Orexin-A (OXA) a neuropeptide can reduce inflammation and neurodegeneration. The immunomodulatory role OXA in the hippocampus and in cognitive decline is unknown. We hypothesized that OXA effects on cognition are due in part by immunomodulation of microglia. To test this, we pre-treated immortalized mouse microglia with OXA (300 nM) and then challenged with PA (0.1 mM; 4h). Gene expression for arginase-1 (anti-inflammatory marker; via qRT-PCR) and TNF-α secretion (via ELISA) were measured. In O/A3 mice (deficient in OXA) we tested cognitive function using a two-way active avoidance memory task. OXA attenuated PA induced TNF-α secretion (p < 0.0001) and upregulated arginase-1 (p < 0.001). O/A3 mice showed a significant impairment in cognitive performance as compared to wild-type mice (p < 0.05). Future studies will use a rodent pharmacogenetic model of neuromodulation (designer receptors exclusively activated by designer drugs; DREADDs), to directly activate OXA neurons. We will determine if increased orexin signaling will reduce HFD-induced cognitive decline via reduced microglial inflammation. These results would support a pivotal role for OXA immunomodulation in the context of obesity and cognitive decline.
Funder Acknowledgement(s): Funding was provided by North Star STEM Alliance program and Minnesota’s Discovery, Research and innovation Economy (MnDrive ). VA Office of Research and Developments: RR&D RX000441, NIDDK R01 DK100281 (to CMK), BLR&D BX001686 (to TAB), Minnesota Obesity Center Grant P30 DK050456 (to TAB).
Faculty Advisor: Tammy Butterick, Butte017@umn.edu
Role: I did Real-Time qRT-PCR to determine relative mRNA expression of target gene after LPS stimulation of microglial cells. I also did Cell Culture of microglial cells and ELISA(enzyme-linked immunosorbent assay).