Alzheimer's disease (AD) is the most common cause of dementia in the elderly, afflicts 1 in 8 elderly Americans, and care for AD patients incurs diret costs of approximately $200 billion annually. There is currently no effective therapy to delay AD onset or slow AD progression. Therefore, it is of critical importance to develop a better understanding of AD pathogenesis in order to develop new targets for therapeutic intervention. AD is characterized by the deposition of aggregated forms of amyloid (A?) plaques within the brain, which is hypothesized to be a critical instigator of synaptic loss and neurodegeneration. The strongest genetic determinant for the development of the most common form of AD, late onset AD, is possession of the apolipoprotein E 4 allele (APOE4). ApoE is a critical lipid transport protein in the CNS where it is expressed mainly by astrocytes. There are three common apoE variants (apoE2, apoE3, and apoE4) which differentially regulate A? clearance from the CNS and A? plaque formation. Little is known about the physiological regulation of apoE within the CNS, particularly in regard to the regulation of the levels and lipidation of the extracellular pool of apoE. We recently developed a method to measure the level and lipidation state of apoE directly from the brain parenchyma interstitial fluid (ISF) using in vivo microdialysis. Since neurons rely upon apoE to supply lipids and cholesterol to support neuronal function, we decided to test whether synaptic activity modulated apoE within the brain. Our preliminary data indicate that increasing synaptic activity increases the ISF level of apoE. Interestingly, synaptic activity has previously been shown to regulate A? production and A? ISF level. Therefore, we propose use in vivo microdialysis to investigate whether synaptic activity co-regulates apoE and A? within the ISF, and whether synaptic activity-dependent regulation of apoE level and lipidation impacts fluctuations in A? levels during physiological changes in neuronal activity, such as during the sleep- wake cycle. The results of our experiments will further our understanding of apoE regulation within the CNS and could provide insight for the development of novel AD therapies to reduce the burden of neurological disease.