Project 1. Glabe. Diversity of Amyloid Oligomer Assembly States and Roles in AD PathogenesisThe goal of this research project is to explore the mechanisms of amyloid deposition and the role of distinctassembly states of amyloid oligomers in pathogenesis in AD and in transgenic mouse models of AD. Severaldifferent types of amyloid deposits accumulate in disease brain and current evidence suggests that different typesof amyloid assembly states may play distinct roles in pathogenesis. We have produced three differentconformation-dependent antibodies that specifically recognize prefibrillar oligomers, fibrils and pore-like annularprotofibrils that are formed from many different types of amyloids. We hypothesize that these threeconformationally distinct assembly states of AC are differentially associated with AD pathogenesis. We will testthe hypothesis that soluble, oligomeric or annular forms of AB are primarily associated with neuronal dysfunctionand AD and DS pathogenesis. We will determine the distribution, localization and concentration of prefibrillar,annular and fibrillar amyloid deposits in several different regions of human AD brain, mild cognitively impairedand age-matched control brains. We will determine the localization and concentration of soluble oligomers,annular protofibrils and mature fibrils in transgenic animals as a function of age and examine the effect ofvaccination against oligomeric and fibrillar forms of AC on the accumulation of different types of amyloid. Wewill biochemically characterize the various types of soluble oligomers from AD brain to determine theirrelationship to the various conformations of AC formed in vitro and we will compare their toxicity and interactionwith neurons in vitro. The hypothesis is that the oligomers in human AD brain are related to one or more of thedifferent conformations in vitro oligomers, but may also contain other components that either enhance or inhibittheir toxicity in vitro. We anticipate that these results will help clarify which assembly states of amyloid areprimarily associated with AD pathogenesis and resolve some apparent inconsistencies and conflicting data, suchas the observations that the total AC amyloid deposited correlates poorly with disease and some people have largeamounts of amyloid and are cognitive normal, while other brain samples that have little observable amyloiddeposits are associated with cognitive dysfunction. The availability of pure and homogeneous populations ofdifferent assembly states of AC and novel antibodies that specifically recognize these different assembly statesaffords us a unique opportunity to examine and clarify the role of AC assembly states in Alzheimer diseasepathogenesis.
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