We hypothesize that amyloid beta-protein (A-beta) assembly into oligomers and polymers is a seminal neuropathogenetic process in Alzheimer's disease (AD) and in cerebral amyloid angiopathy (CAA). Inhibiting formation of, or disrupting, A-beta assemblies thus could be of benefit in the treatment of these disorders. To test this hypothesis, a detailed mechanistic knowledge of the assembly process is necessary. Our previous work towards this goal revealed the existence of protofibrillar fibrillogenesis intermediates. These have been found to be neurotoxic in vitro. Recently, in collaborative studies with the Lannfelt group, we reported that protofibrils may be the causative agents in an """"""""Arctic"""""""" form of AD. Thus, a concordance of results from fundamental studies of A-beta assembly in vitro with those from clinical investigations in humans supports the involvement of prefibrillar assemblies in AD pathogenesis. In order to understand the structural and thermodynamic principles underlying the formation of these toxic A-beta assemblies, rigorous in vitro studies are necessary. This elucidation process should facilitate later rational design and testing of therapeutic agents. Here, we seek to delve deeply into the thermodynamics and structural biology of early A-beta assembly reactions in order to understand the fundamental factors controlling these processes and to identify and characterize the structures formed. These structures include small prenuclear oligomers, larger micelle-like oligomers, fibril nuclei, and protofibrils. Importantly, knowledge gained regarding the kinetics of formation and the stability of these assemblies will be used to enable functional assays of the biological effects of the assemblies. We propose to accomplish these goals in the context of the following four interconnected aims.
Aim 1. To elucidate the thermodynamics of A-beta fibril formation at neutral pH.
Aim 2. To determine the structural features of early A-beta assemblies.
Aim 3. To determine the mechanism of transformation of early A-beta assemblies into fibril nuclei.
Aim 4. To determine the biological activity of early intermediates.
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