One of the profound factors for the cause of Alzheimer's disease (AD) is overexpression and the presence of soluble amyloid beta (Aβ) oligomers in human brain neural cells. The goal of this work is to characterize the molecular interactions between Aβ-40/Aβ-42 and different Ig-like domains of PirB/LilrB2 ectodomain, since the interaction of these species negatively influences synaptic strength and memory in a mouse model. It is hoped that the structural information gathered will lead to the development of therapeutic molecules that can specifically block LilrB2 function.
Amyloid-beta (Aβ) oligomers are involved in the impairment of synaptic plasticity that leads to synaptic loss in human Alzheimer's disease (AD) brains. Recently, Kim et al. (Science, 2013) reported the novel murine PirB (paired Ig-like receptor B) and its human ortholog LilrB2 (leucocyte Ig-like receptor B) as potential receptors for Aβ oligomers. The extracellular ectodomains of PirB and LilrB2 contain 4 and 6 Ig-like domains, respectively. The mouse model study of the PirB-Aβ system showed deleterious effects on hippocampal long-term potentiation, memory defects and synaptic loss in visual cortex. Previously, Aβ was shown to interact with PrPc (cellular prion protein) and ephrin type B receptor 2(EphB2) molecules.
In order to understand the molecular interactions between Aβ-40/Aβ-42 and different Ig-like domains of PirB/LilrB2 ectodomain need to be characterized. In this project, various constructs of PirB/LilrB2 are being expressed and purified for structural studies by X-ray crystallography and/or electron microscopy. At the same time, functional studies are being optimized to determine the binding affinities (Kd) between the components in-vitro via SPR and fluorescence measurements.