Lead Exposure and Beta-Amyloid Transport by Brain Barriers

铅暴露和脑屏障的 β-淀粉样蛋白转运

• 批准号: 9754143
• 负责人: YANSHENG DU
• 金额: $ 38.06万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754143
• 关键词: Abeta clearance; Advanced Glycosylation End Products; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Injuries; Brain region; Carrier Proteins; Cerebrospinal Fluid; Cerebrovascular system; Characteristics; Clinical Research; Coupled; Coupling; Data; Deposition; Development; Diagnosis; Dose; Environmental Exposure; Epigenetic Process; Etiology; Event; Excision; Exposure to; Extracellular Fluid; Extracellular Space; Extravasation; Fluorescence; Future; Gene Expression; General Population; Hand; Homeostasis; Imaging Techniques; Immunohistochemistry; Impairment; In Situ; Infusion procedures; Intercellular Fluid; Intravenous Immunoglobulins; Ions; Knowledge; Late Onset Alzheimer Disease; Lead; Lead Poisoning; Ligands; Lipoprotein Receptor; Liquid substance; Literature; Mediating; Medical Imaging; Metabolic; Metabolism; Metals; Molecular; Mus; Neurons; Pathogenesis; Pathway interactions; Peptides; Perfusion; Permeability; Play; Poison; Process; Reaction; Regional Blood Flow; Research; Roentgen Rays; Role; Senile Plaques; Source; Specialist; Structure; Structure of choroid plexus; Synchrotrons; System; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Vascular Permeabilities; Wild Type Mouse; X-Ray Computed Tomography; abeta accumulation; abeta oligomer; amyloid formation; blood cerebrospinal fluid barrier; bone; brain parenchyma; brain tissue; cell injury; cerebral capillary; cerebral microvasculature; cerebrovascular; chronic Pb exposure; contrast enhanced; design; experimental study; extracellular; fluorescence imaging; in vivo; lead concentration; lead exposure; neurobehavioral test; novel; novel strategies; overexpression; protein transport; receptor

Abstract:   Accumulation of beta‐amyloid (Aβ) 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 AΒ 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 AΒ 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 AΒ at the BBB and BCB, facilitates the physiochemical reactions between AΒ 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 AΒ and have the detectable amyloid plaques in brain as well as WT mice. We will also characterize the shift of fibril AΒ 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 AΒ transporters, i.e., lipoprotein receptor protein‐1 (LRP1) and advanced glycation end products (RAGE) in mediating AΒ transport by mainly the BCB, and how Pb exposure may affect the direction of AΒ 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 AΒ 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 AΒ 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

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