Role of circulating Abeta seeds and peripheral tissue damage in Alzheimer's disease pathogenesis

点击翻译按钮获取中文摘要

Principal Investigator/Program Director (Last, first, middle): Soto, Claudio / Morales, Rodrigo ABSTRACT Several reports using animal models of Alzheimer's disease (AD) suggest that amyloid-beta (Aβ) and tau aggregates can spread across different tissues promoting the appearance of the typical brain lesions observed in this disease. The role of blood and peripheral clearance in the spread of these structures has not been extensively explored. Our preliminary results show that biologically active Aβ oligomeric seeds are present in blood of AD patients and animal models, suggesting that this biological fluid may play an important role in the spreading of the disease. Supporting this data, administration of Aβ aggregates by intra-venous injection accelerates brain amyloidosis in transgenic mice and removal of circulating Aβ aggregates by whole blood exchange dramatically reduces the amount of cerebral amyloid deposits. Our working hypothesis is that blood contributes to the spread of biologically active Aβ oligomeric seeds and that impairment in peripheral clearance mechanisms has significant implications for the etiology and progression of AD. We also propose that the presence of functional Aβ oligomers in blood may enable the development of novel strategies for diagnosis and therapy focusing on the peripheral pool of Aβ aggregates. To test this hypothesis we plan to identify and characterize biologically functional Aβ aggregates in blood of AD patients, using novel in vitro techniques and animal models. Also, we will explore whether abnormalities on peripheral Aβ clearance by acute or chronic liver damage affects the progression of amyloid deposition in models of familial and sporadic AD. Moreover, we will study the translational implication of these findings by attempting to develop novel strategies for diagnosis and treatment based on the idea that misfolded Aβ aggregates are present in blood and contribute to the pathology in the brain. In the diagnostic side, we propose to adapt to Aβ an assay for ultra-sensitive detection of protein aggregates in blood. This assay, termed PMCA, was originally developed in our lab to detect prions and has been widely utilized to identify pathological prions in blood of patients. In the therapeutic side, we propose to perform proof-of-concept studies to analyze the benefit of removing Aβ aggregates from the blood for the pathological and functional abnormalities in the brain. Removal of circulating Aβ aggregates in live animals will be done by plasmapheresis and blood dialysis. The experiments proposed in this project will enable to investigate a possible mechanism for the initiation and progression of what is widely considered as the earliest pathological alteration in AD, i.e. the misfolding, aggregation and cerebral accumulation of Aβ.