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 (A?) 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 A? 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 A? aggregates by intra-venous injection accelerates brain amyloidosis in transgenic mice and removal of circulating A? 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 A? 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 A? oligomers in blood may enable the development of novel strategies for diagnosis and therapy focusing on the peripheral pool of A? aggregates. To test this hypothesis we plan to identify and characterize biologically functional A? aggregates in blood of AD patients, using novel in vitro techniques and animal models. Also, we will explore whether abnormalities on peripheral A? 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 A? aggregates are present in blood and contribute to the pathology in the brain. In the diagnostic side, we propose to adapt to A? 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 A? aggregates from the blood for the pathological and functional abnormalities in the brain. Removal of circulating A? 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 A?.
Soto, Claudio / Morales, Rodrigo PROJECT NARRATIVE Recent reports suggest that the protein aggregates (A? and Tau) which are the pathognomic features of Alzheimer's disease (AD), can spread following a similar mechanism to the one described for prion proteins. The aim of this project is to identify and characterize A? oligomeric aggregates in blood from AD patients, study the contribution of circulating A? oligomers to seed amyloid deposition in the brain and investigate whether impairments in peripheral A? clearance influence the progression of the pathological abnormalities in the brain. The outcomes obtained from these studies could change the current view about the etiopathogenesis of AD and uncover new therapeutic and diagnostic strategies.
