Accumulation of beta?amyloid (A?) 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) between the blood and brain interstitial fluid and the blood-CSF barrier (BCB) between the blood and cerebrospinal fluid (CSF) play an important role in maintaining the homeostasis of A? in brain extracellular milieu. Since the brain barrier systems are the known targets of Pb toxicity, it is quite possible that Pb toxicity on brain barriers may affect the critical processes in brain barrier systems that regulate A? transport and metabolism. Thus, the central hypothesis to be tested in this study is that exposure to Pb damages the brain barrier systems, which compromises the clearance and eventually increases the leakage of A? at the BBB and BCB, facilitates the physiochemical reactions between A? 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 sets of 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 Tg?APP mice which overexpress A? and have the detectable amyloid plaques in brain as well as WT mice. We will also characterize the shift of fibril A? 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 transporters, RAGE and LRP?1, in the BBB treated with Pb. The experiments in Aim 2 will focus on the role of two A? transporters, i.e., lipoprotein receptor protein?1 (LRP1) and advanced glycation end products (RAGE) in mediating A? transport by mainly the BCB, and how Pb exposure may affect the direction of A? transport across the BCB. Finally, in Aim 3, we will use synchrotron X?ray fluorescence (XRF) imaging technique coupled with immunohistochemistry to co? localize Pb with amyloidal aggregates and K X?ray fluorescence (KXRF) technique quantify real?time Pb concentrations in bone (PbBn) and to establish the association between PbBn and amyloid aggregation 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 brain A? oligomers and plaques as well as in blood vessels. We will also establish the relationship between Pb exposure and permeability changes of brain barriers to A? fluxes and provide clues as to whether chronic Pb exposure and changes in cerebral vascular permeability contribute to AD pathogenesis and development. The research will help develop the novel strategies for diagnosis, treatment and prevention of AD. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page
Statement: This study, by teaming together neurotoxicologist, molecular neurobiologist, medical imaging specialist and synchrotron physicist, will explore novel pathways of Pb?affected A? transport by brain barrier systems and will define the role of Pb exposure in AD pathogenesis. Results of this study will provide clues as to whether exposure to toxic Pb in the general population may contribute to the AD etiology. Potential discovery of A? transporters and metabolic regulatory mechanism in the brain barrier systems will help develop novel strategies for diagnosis, treatment and prevention of Alzheimer's disease. PHS 398/2590 (Rev. 06/09) Page 2 Continuation Format Page
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