👤 Luis B Tovar-Y-Romo

Microglia are the innate immune cells of the brain. Recent single cell and nucleus sequencing along with other omics technologies are leading the way for new discoveries related to microglial function and diversity. The Nogo-signaling system is a prime target for investigation with these tools as it has previously been neglected in microglia. The Nogo-signaling system consists of approximately 20 proteins, including ligands, receptors, co-receptors, and endogenous inhibitors known for their neuronal plasticity restricting properties via RhoA and ROCK1/ROCK2 activation, and have recently been implicated in microglial function. Here, we explore expression patterns of Nogo-family genes in the mouse and human brain. In mice, we focus on brain cell type enrichment, patterns of expression in microglia from embryonic stages to adulthood, sex differences, and changes in expression in acute and chronic inflammatory contexts from publicly available RNAseq and RiboTag translational profiling datasets. We identified differential expression of Nogo-family genes across age, sex, and disease/injury in mice. To analyze human microglia, we utilize a new tool, the Show less

Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders. Show less