Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice

Although soluble oligomeric and protofibrillar assemblies of Abeta-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Abeta-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds 'forward' in a near-irreversible manner from the monomeric Abeta peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Abeta amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Abeta but rather toward soluble amyloid protofibrils. We characterized these 'backward' Abeta protofibrils generated from mature Abeta fibers and compared them with previously identified 'forward' Abeta protofibrils obtained from the aggregation of fresh Abeta monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Abeta-aggregates that could readily be activated by exposure to biological lipids.     

Seeing 'where' through the ears: effects of learning-by-doing and long-term sensory deprivation on localization based on image-to-sound substitution

Background

Sensory substitution devices for the blind translate inaccessible visual information into a format that intact sensory pathways can process. We here tested image-to-sound conversion-based localization of visual stimuli (LEDs and objects) in 13 blindfolded participants.

Methods and Findings

Subjects were assigned to different roles as a function of two variables: visual deprivation (blindfolded continuously (Bc) for 24 hours per day for 21 days; blindfolded for the tests only (Bt)) and system use (system not used (Sn); system used for tests only (St); system used continuously for 21 days (Sc)). The effect of learning-by-doing was assessed by comparing the performance of eight subjects (BtSt) who only used the mobile substitution device for the tests, to that of three subjects who, in addition, practiced with it for four hours daily in their normal life (BtSc and BcSc); two subjects who did not use the device at all (BtSn and BcSn) allowed assessment of its use in the tasks we employed. The impact of long-term sensory deprivation was investigated by blindfolding three of those participants throughout the three week-long experiment (BcSn, BcSn/c, and BcSc); the other ten subjects were only blindfolded during the tests (BtSn, BtSc, and the eight BtSt subjects). Expectedly, the two subjects who never used the substitution device, while fast in finding the targets, had chance accuracy, whereas subjects who used the device were markedly slower, but showed much better accuracy which improved significantly across our four testing sessions. The three subjects who freely used the device daily as well as during tests were faster and more accurate than those who used it during tests only; however, long-term blindfolding did not notably influence performance.

Conclusions

Together, the results demonstrate that the device allowed blindfolded subjects to increasingly know where something was by listening, and indicate that practice in naturalistic conditions effectively improved “visual” localization performance.     

Effect of weak static and low-frequency alternating magnetic fields on the fission and regeneration of the planarian dugesia (Girardia) tigrina

The effect of weak static (DC) and alternating (AC) magnetic fields (MFs), as well as combined (AC/DC) collinear MFs on the intensity of morphogenesis processes in the planarian Dugesia (Girardia) tigrina has been studied. It was found that combined MFs produce a stimulating effect on the fission and regeneration of planarians. Both components of the combined MFs, the direct (DC) and the alternating (AC), are important in the realization of the effects of weak MFs. The practically complete absence of one of the components (DC) reverses the sign of the effect. It was shown that the presence of concomitant background MFs does not substantially influence the effects of combined MFs with a very small AC component (100 nT). The effect of the "zero" field is significant and comparable in magnitude with the effects of combined MFs at effective frequencies. Narrow zones of effective amplitudes (in the region of tens and hundreds of nT) of the AC component of the combined MFs, with the DC component close to the value of the geomagnetic field were found, which alternate with regions where the response of the biological object to the influence is absent.     

Tjp3/zo-3 is critical for epidermal barrier function in zebrafish embryos

TJP3/ZO-3 is a scaffolding protein that tethers tight junction integral membrane proteins to the actin cytoskeleton and links the conserved Crumbs polarity complex to tight junctions. The physiological function of TJP3/ZO-3 is not known and mice lacking TJP3/ZO-3 show no apparent phenotype. Here we show that Tjp3/Zo-3 is a component of tight junctions present in the enveloping cell layer of zebrafish embryos. Silencing tjp3/zo-3 using morpholinos leads to edema, loss of blood circulation and tail fin malformations in the embryos. The ultrastructure of tight junctions of the enveloping cell layer is disrupted, without affecting the asymmetric distribution of plasma membrane proteins. Morphants show a loss of the epidermal barrier, as assessed by an increased permeability of the enveloping cell layer to low molecular weight tracers and a higher sensitivity of the embryos to osmotic stress. Subjecting wild-type embryos to osmotic stress mimicks the morphant phenotype, consistent with the phenotype being a direct consequence of failed osmoregulation. Thus, Tjp3/Zo-3 is critical for barrier function of the enveloping cell layer and osmoregulation in early stages of zebrafish development.     

Effects of neuropeptide F on regeneration in <Emphasis Type="Italic">Girardia tigrina</Emphasis> (Platyhelminthes)

The effects of neuropeptide F (NPF; from Moniezia expansa) on the regeneration of Girardia tigrina were studied. The animals were decapitated and incubated in water (control) or NPF. The dynamics of the proliferation of the neoblasts in the developing tissue were studied during the course of regeneration by monitoring the mitotic index (MI). The effects of incubation in FMRFamide and GYIRFamide on the MI were also tested. The course of cephalic regeneration was followed with in vivo computer-assisted morphometry for up to 7 days. The development of the regenerating nervous system and the musculature was visualised by immunostaining with a primary antiserum to the C-terminal decapeptide of NPF (YFAIIGRPRFa) and tetramethylrhodamine-isothiocyanate-conjugated phalloidin, which stains F-actin in muscle filaments. The study showed that NPF had a stimulatory effect on the mitotic activity of the neoblasts. FMRFamide and GYIRFamide did not have this effect. NPF also stimulated the growth of the regenerating head and the growing nervous system and musculature. NPF is postulated to have a morphogenetic action in the regenerating animals. This work was supported by two grants from the Finnish Academy of Science (nos. 202685, 2004) and (no. 112090, 2006) to M.G., an RFBR grant (07-04-00452a) to N.K. and a Wellcome Trust grant (069411) to A.G.M. for which we express our gratitude.     

A new UV-B absorbing mycosporine with photo protective activity from the lichenized ascomycete Collema cristatum.

A novel photo protective mycosporine was isolated from the lichenized ascomycete Collema cristatum. Biological activity was measured in terms of protection against UV-B induced membrane destruction and pyrimidine dimer formation in cultured human keratinocytes, and prevention of UV-B induced erythema. It was found that the pure isolated compound prevented UV-B induced cell destruction in a dose-dependent manner, that the compound partially prevented pyrimidine dimer formation and completely prevented UV-B induced erythema when applied to the skin prior to irradiation.     

N-glycosylation modulates the cell-surface expression and catalytic activity of corin

N-Glycosylation may influence the subcellular localization and biological activity of the pro-ANP convertase, corin. In HEK293-corin cells, the inhibition of N-glycosylation, with tunicamycin, reduced the cell-surface expression of murine corin, but did not alter the total expression. Therefore, tunicamycin treatment likely caused the intracellular accumulation of non-glycosylated corin. Tunicamycin treatment also significantly reduced corin activity (pro-ANP cleavage) in these cells. We developed an assay to measure the effect of N-glycosylation on corin activity, independent of its effect on corin localization. We determined that the reduction in corin activity was due to a direct effect of N-glycosylation, and was not secondary to the effect of N-glycosylation on corin cell-surface expression. Our data provide evidence that N-glycosylation is essential for the cell-surface expression of murine corin and modulates its functional activity. N-Glycosylation represents a possible mechanism for the regulation of native corin on the surface of cardiomyocytes.