Project Summary /Abstract Accumulation of beta-amyloid (AP) in brain extracellular parenchyma and fluid is the key event in the amyloid cascade leading to neuronal cell damage in the etiology of Alzheimer's disease (AD), The blood-brain barrier (BBB) and the blood-CSF barrier (BCB) play an important role in maintaining the homeostasis of AP in brain extracellular milieu. Pb toxicity on brain barriers may affect the critical processes in brain barrier systems that regulate AP transport and metabolism Thus, the central hypothesis is that exposure to Pb damages the brain barrier systems, which compromises the clearance and eventually increases the leakage of AP at the BBB and BCB, facilitates the physiochemical reactions between AP and Pb ions, ultimately leading to an increased formation of amyloid plaques in both brains and blood vessels. To test this hypothesis, we have designed three specific aims. In aim 1, we will use the state-of-the-art dynamic contrast-enhanced computed tomography (DCE-CT) to quantify the real-time brain regional blood flow, blood volume, and BBB permeability before and after Pb exposure in TgAPP mice develop brain amyloid plaques as well as WT mice. We will also characterize the shift of fibril AP deposits from the brain's capillary vessels to its parenchyma as a result of Pb exposure in a dose-time dependent fashion. We will focus on expressions of two AP transporters, i.e., lipoprotein receptor protein-1 (LRPl) and advanced glycation endproducts (RAGE), in the BBB treated with Pb. Aim 2 will focus on the role of RAGE and LRP- lin mediating AP transport by mainly the BCB. In Aim 3, we will use synchrotron X-ray fluorescence (XRF) imaging technique coupled with immunohistochemistry to co-localize Pb with amyloid aggregates and K X-ray fluorescence (KXRF) technique quantify real-time Pb concentrations in bone (PbBn) to establish the association between PbBn and amyloid in brain and blood vessels after Pb exposure at different doses and time. These studies will establish a novel concept that the brain barriers play a key role in regulating Pb-induced AP oligomers and plaques in brain and blood vessels by investigating the relationship between Pb exposure and permeability changes of brain barriers to AP fluxes and provide clues as to whether chronic Pb exposure and changes in cerebral vascular permeability contribute to AD pathogenesis and development.