The amyloid ?-protein is implicated as a key pathogenic molecule in the pathogenesis of Alzheimer's disease (AD) and related disorders. A? possesses the strong propensity to self-assemble into soluble, oligomeric species and ultimately into insoluble, fibrillar structures that deposit in the central nervous system. Although soluble A oligomeric assemblies and A? deposits exist largely in the extracellular compartment of the CNS growing evidence suggests that initial assembly stages of A? and potential sites for its toxic activities occurs within neurons suggesting that this may be an early site for targeting the disruption of this process. However, our present understanding of what regulates these processes in the CNS, in particular within neurons, remains incomplete. Recently, we identified myelin basic protein (MBP) as a novel factor isolated from brain that can strongly bind to A? peptides and potently inhibit their assembly into fibrils and its neurotoxicity. Moreover, this particular function of MBP was mapped to N-terminal residues 1-64 (MBP1-64), a region that is contained in most related Golli proteins as well. In addition to its prominent role in myelin sheat formation, Golli-MBP proteins are present in numerous cells, including neurons, and have been proposed as intracellular multifunctional scaffolds that can bind a number of intracellular proteins and small molecule ligands affecting diverse cellular processes. In light of these points the overall hypothesis of this exploratory proposal is that Golli-MBP proteins interact with intracellular A? peptides to influence their assembly, accumulation, and toxicity within neurons and extracellularly in the brain. In the present proposal we plan to implement a multi-faceted approach to investigate how a biologically active MBP fragment interacts with A? peptides both in vitro and in vivo to regulate their intracellular and extracellular assembly, deposition, and pathological consequences. First, we will utilize cultured cortical neurons prepared from Tg-5xFAD mice that produce high levels of intracellular and extracellular A? peptides in vitro. We will express the MBP1-64 fragment in these neurons to investigate how it influences the fate of intracellular A? peptide. Second, we will use the well-characterized Tg-5xFAD mice that exhibit intraneuronal A? and develop abundant, age-dependent extracellular A? plaque deposits with accompanying neuroinflammation and behavioral deficits. The Tg-5xFAD mice will be crossed with newly generated transgenic mice that express the biologically active MBP1-64 fragment in neurons to investigate its interaction with A? peptides and how this might alter pathological outcomes. Completion of these studies will provide new insight into the biology of intracellular Golli-MBP interactions with A? that may contribute to the spatial and quantitative regulation of A? levels, assembly, and deposition in brain as well as the accompanying downstream pathological consequences.
Assembly and deposition of a protein fragment, known as amyloid ? -protein (A?), in the brain is a key pathological feature of Alzheimer's disease and related disorders. Factors that regulate its assembly play an important role in determining if and where A? accumulates during disease. The purpose of this proposal is to investigate the activity of a newly identified factor, myelin basic protein (MBP), on A? assembly and deposition in cultured neuronal cells and in brain using a mouse model of intraneuronal and extracellular A? accumulation.
|Ou-Yang, Ming-Hsuan; Xu, Feng; Liao, Mei-Chen et al. (2015) N-terminal region of myelin basic protein reduces fibrillar amyloid-? deposition in Tg-5xFAD mice. Neurobiol Aging 36:801-11|
|Kotarba, Annmarie E; Aucoin, Darryl; Hoos, Michael D et al. (2013) Fine mapping of the amyloid ýý-protein binding site on myelin basic protein. Biochemistry 52:2565-73|
|Ou-Yang, Ming-Hsuan; Van Nostrand, William E (2013) The absence of myelin basic protein promotes neuroinflammation and reduces amyloid ?-protein accumulation in Tg-5xFAD mice. J Neuroinflammation 10:134|