A major theme of this project is understandli>g the causes and condittons that lead to a state of chronic up-regualtion of pro-inflammatory process in aging that are the backround within whk:h neurodegeneartivedisease occurs. We have demonstrated that loss of the chemokine fractalkine (FKN) is an early event inbrain aging and that this precipitates a bias towards pro-inflammatory signals such as ILI3 and TNFa.Fractalkine (CX3CL1) is expressed in neurons and the receptor (CX3CR1) is on microglia. Ligation ofCX3CR1 resullts in down regulation of 11-1 p, TNFa and other pro-inflammatory cytokines. We will examineregulation of CX3CL1 as it is present as both a cleaved soluble fonn and a membrane bound fomi. There isevidence that the membrane bound form and the soluble forni control different aspects of immune regulation,however this is poorly understood. To address this questton we have generated rAAVQ vectors that express1 )soluble, 2) native and 3) a mutant uncleaved CX3CL1. We wUI use these unique and novel tools tounderstand the role these forms of FKN in control of microglial function and its role to regulate neuralplasticity measured as neurogensis and long term potentiaion (LTP) and cf^ntiive function in aged mice andCX3CL1 deficient mice to dtermine if replacement of FKN at an early age (12 months) will lead to kinglasting regulation of microglial function and prevent increased innate immune function with age and preverit aloss in neural plasticity and cognitive function.
In aim 2 we will examine if neurr^l specify versus astrocytespecific expression of CX3CL1 alters the functional properties. CX3CL1 is normally epxressed in nuerons,hoever under certain condittons it has t)een observed in astrocytes.
In aim 3 we will then look further at therole of CX3CL1 and its receptor as it may interact with Ml and M2 responses to stimuli with age, as we haveobsen^ed blunted responses to iL4/IL13 in the aged brain. We will examine this in tfie CX3CR1 null andCX3CL1 null mice as well as nonnai aged C57BL/6 mice. We will isolate primary microglia for ex vivo cellculture experiments to detemnine if any changes in regulation of l^1 and M2 responses are cell autonomousor non cell autononwus.
Aging is a primary risk factor for many neurodegenerative diseases and also can be associated withcognitive slowir^. Understanding key molecules in the brain that underly changes in brain aging that makethe brain more suceptible to disease is critical and can lead to new approacfies to reduce the incidence orseverity of neurodegenerative diseases and declines in cognitive function with age
