Alzheimer’s disease (AD) is devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is the hypothesis that a viral infection is a key to the etiology of late-onset AD with amyloid Aβ peptides playing a protective role. Contrary to previous work, in the current study 5XFAD genotype failed to protect mice against infection with two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae. Moreover, the region- or cell-specific tropisms of HSV-1 were not affected by 5XFAD genotype arguing that the host-pathogen interactions were not altered.Aged 5XFAD mice with abundant Aβ showed only a modest, statistically non-significant delay in response to acute HSV-1 infection. While the current study questions the antiviral role of APP or Aβ, it does not support nor dismiss the hypothesis on viral etiology of late-onset AD.
The epidermal growth factor receptor (EGFR) is one of the most extensively studied receptor tyrosine kinases, as it is involved in a wide range of cellular processes and severe diseases. Recent works reveal that the single-helix transmembrane domains and cytoplasmic juxtamembrane regions play an important role in the receptor activation process. Here we present the results of our investigation of the spatial structure and mobility of the EGFR transmembrane domain and juxtamembrane regions in various membranelike environments, which shed light on the effects of the membrane physical properties and composition on the behavior of the juxtamembrane domain.
In the present work we consider the inverse problem of identification the spherical cavity of small relative size in the isotropic elastic cylinder. Based on the methods of perturbation theory, analytical formulas for determining the parameters of the cavity have been obtained using information concerning corrections to the natural frequencies. A series of numerical experiments has been carried out.
In recent studies, the amyloid fibrils produced in vitro from recombinant prion protein encompassing residues 89−230 (rPrP 89−230) were shown to produce transmissible form of prion disease in transgenic mice (Legname et al., (2004) Science 305, 673−676). Long incubation time observed upon inoculation of the amyloid fibrils, however, suggests that the fibrils generated in vitro have low infectivity titers. These results emphasize the need to define optimal conditions for prion conversion in vitro, under which high levels of infectivity can be generated in a cell-free system. Because copper(II) has been implicated in normal and pathological functions of the prion protein, here we investigated the effect of Cu2+ on cell-free conversion of recombinant PrP. Our results show that at pH 7.2 and at micromolar concentrations, Cu2+ inhibited conversion of full-length recombinant PrP (rPrP 23−230) into amyloid fibrils. This effect was most pronounced for Cu2+, and less so for Zn2+, while Mn2+ had no effect on the conversion. Cu2+-dependent inhibition of the amyloid formation was less effective at pH 6.0, at which rPrP 23−230 displays lower Cu2+-binding capacity. Using rPrP 89−230, we found that Cu2+-dependent inhibition occurred even in the absence of octarepeat region; however, it was less effective. Our further studies indicated that Cu2+ inhibited conversion by stabilizing a nonamyloidogenic PK-resistant form of α-rPrP. Remarkably, Cu2+ also had a profound effect on preformed amyloid fibrils. When added to the fibrils, Cu2+ induced long-range coiling of individual fibrils and enhanced their PK-resistance. It, however, produced only minor changes in their secondary structures. In addition, Cu2+ induced further aggregation of the amyloid fibrils into large clumps, presumably, through interfibrillar coordination of copper ions by octarepeats. Taken together, our studies suggest that the role of Cu2+ in the pathogenesis of prion diseases is complex. Because Cu2+ may inhibit prion replication, while at the same time stabilize disease-specific isoform against proteolytic clearance, the final outcome of copper-induced effect on progression of prion disease may not be straightforward.
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