Neurodegenerative diseases of human aging are significant US health burdens due to the growing number of people living with dementia. Many disorders like Alzheimer's disease are associated with excess brain iron that accumulates with age. Such observations have led to the metal theory of dementia, which suggests that over time, environmental exposure to iron promotes neurodegeneration. We have discovered that ?9-THC and other cannabinoids inhibit the iron transporter divalent metal transporter-1 (DMT1) through cannabinoid receptor-2 (CB2). CB2 is an immunomodulatory receptor and its anti-inflammatory neuroprotective effects confer suppression of microglia activation. Microglial cells act as the immune cells of the brain and spinal cord, becoming activated by changes in their local microenvironment. Microglia polarize between reactive and repair states to actively transition from an immune-stimulating antimicrobial phenotype to one that supports tissue repair and resolution of inflammation. SPECIFIC AIM 1: Determine mechanisms of microglial iron transport and metabolism. We have determined that IMG cell iron uptake corresponds to the M1/M2 activation state of IMG cells. While more non-transferrin (Tf) bound iron (NTBI) is taken up by LPS-treated cells, Tf-mediated transport is increased by IL-4. Based on our data, we hypothesize that microglial cell polarization directs iron trafficking. We will: a) Test the hypothesis that microglial cell polarization controls uptake and metabolic partitioning of iron into subcellular compartments; and b) Test the hypothesis that IMG cell activation by A? alters microglia metabolism by up- regulating DMT1 activity and dysregulating energy metabolism. SPECIFIC AIM 2: Determine influence of CB2 on microglial iron transport and metabolism. We have determined the CB2 selective agonist JWH102 reduces the pro-inflammatory activation state of IMG cells promoted by A?. We have also found that CB2 promotes dephosphorylation of DMT1 to block its activation. Based on our data, we hypothesize that CB2 redirects iron trafficking and cellular metabolism by regulating DMT1 phosphorylation. We will: a) Test the hypothesis that the CB2 selective agonist JWH102 reduces NTBI iron transport and shifts energy metabolism in LPS and A?-activated IMG cells; and b) Test the hypothesis that CB2 regulates DMT1 phosphorylation to control is activity in IMG cells.