👤 Chesney R Brock

Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms. Show less

Glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and G protein-coupled receptor 40 (GPR40) are members of G protein-coupled receptors (GPCR) family. They are abundantly expressed in islet beta cells, and mediate effects of incretins and fatty acids in beta cells. Glucose and 5-AMP-activated protein kinase (AMPK) are known to be involved in the regulation of beta cell function. Metformin and the potential therapeutic drug for type 2 diabetes, 5-amino-4-imidazolecarboxamide riboside (AICAR), are both known activators of AMPK. Here we studied the effects of glucose, metformin, and AICAR on the expression of GPCR in INS-1 beta cell. INS-1 beta cells were supplemented with different concentrations of glucose, metformin, or AICAR. The expressions of GLP-1R, GIPR, GPR40, and a nuclear transcription factor - peroxisome-proliferator activated receptor alpha (PPARalpha) - were analyzed by real-time RT-PCR and immunoblotting. The time-course of the mRNA degradation of these receptors was also monitored by applying actinomycin D to cells. We demonstrated that the expressions of GLP-1R, GIPR, and PPARalpha were downregulated when INS-1beta cells were treated with glucose, while their expressions were upregulated when treated with metformin or AICAR. Glucose, metformin, or AICAR treatment had no obvious effect on the expression of GPR40. These results indicate that glucose, metformin, and AICAR regulated the expressions of incretin receptors and PPARalpha, but not GPR40 in beta cells. Whether AMPK is a key regulator of these factors mediated receptor regulation remains to be investigated further. Show less