Alzheimer disease is characterized by accumulation of the ␤-amyloid peptide (A␤) generated by ␤-and ␥-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing ␤-and ␥-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of ␣-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in ␥-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing A␤ release. DHA has a typical pleiotropic effect; DHA-mediated A␤ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

a b s t r a c tHeat stress is a common and, therefore, an important environmental impact on cells and organisms. While much attention has been paid to severe heat stress, moderate temperature elevations are also important. Here we discuss temperature sensing and how responses to heat stress are not necessarily dependent on denatured proteins. Indeed, it is clear that membrane lipids have a pivotal function. Details of membrane lipid changes and the associated production of signalling metabolites are described and suggestions made as to how the interconnected signalling network could be modified for helpful intervention in disease.

The classic heat shock (stress) response (HSR) was originally attributed to protein denaturation. However, heat shock protein (Hsp) induction occurs in many circumstances where no protein denaturation is observed. Recently considerable evidence has been accumulated to the favor of the "Membrane Sensor Hypothesis" which predicts that the level of Hsps can be changed as a result of alterations to the plasma membrane. This is especially pertinent to mild heat shock, such as occurs in fever. In this condition the sensitivity of many transient receptor potential (TRP) channels is particularly notable. Small temperature stresses can modulate TRP gating significantly and this is influenced by lipids. In addition, stress hormones often modify plasma membrane structure and function and thus initiate a cascade of events, which may affect HSR. The major transactivator heat shock factor-1 integrates the signals originating from the plasma membrane and orchestrates the expression of individual heat shock genes. We describe how these observations can be tested at the molecular level, for example, with the use of membrane perturbers and through computational calculations. An important fact which now starts to be addressed is that membranes are not homogeneous nor do all cells react identically. Lipidomics and cell profiling are beginning to address the above two points. Finally, we observe that a deregulated HSR is found in a large number of important diseases where more detailed knowledge of the molecular mechanisms involved may offer timely opportunities for clinical interventions and new, innovative drug treatments. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Aging and pathophysiological conditions are linked to membrane changes which modulate membrane-controlled molecular switches, causing dysregulated heat shock protein (HSP) expression. HSP co-inducer hydroxylamines such as BGP-15 provide advanced therapeutic candidates for many diseases since they preferentially affect stressed cells and are unlikely have major side effects. In the present study in vitro molecular dynamic simulation, experiments with lipid monolayers and in vivo ultrasensitive fluorescence microscopy showed that BGP-15 alters the organization of cholesterol-rich membrane domains. Imaging of nanoscopic long-lived platforms using the raft marker glycosylphosphatidylinositol-anchored monomeric green fluorescent protein diffusing in the live Chinese hamster ovary (CHO) cell plasma membrane demonstrated that BGP-15 prevents the transient structural disintegration of rafts induced by fever-type heat stress. Moreover, BGP-15 was able to remodel cholesterol-enriched lipid platforms reminiscent of those observed earlier following non-lethal heat priming or membrane stress, and were shown to be obligate for the generation and transmission of stress signals. BGP-15 activation of HSP expression in B16-F10 mouse melanoma cells involves the Rac1 signaling cascade in accordance with the previous observation that cholesterol affects the targeting of Rac1 to membranes. Finally, in a human embryonic kidney cell line we demonstrate that BGP-15 is able to inhibit the rapid heat shock factor 1 (HSF1) acetylation monitored during the early phase of heat stress, thereby promoting a prolonged duration of HSF1 binding to heat shock elements. Taken together, our results indicate that BGP-15 has the potential to become a new class of pharmaceuticals for use in ‘membrane-lipid therapy’ to combat many various protein-misfolding diseases associated with aging.

No abstract

In the context of the current global warming, an increase in the global temperature and in the frequency and severity of heat waves is expected to affect crops productivity and distribution. [1][2][3][4] Land plants constantly encounter wide daily and seasonal thermal variations and the agricultural yields are tightly correlated to their effective tolerance to thermal stress. 5,6 To face this environmental challenge and develop new strategies, it is crucial to fully understand the mechanisms by which mild variations in ambient temperature are accurately perceived, leading to a timely activation of the heat shock proteins (HSPs) and the establishment of an optimal thermotolerance. Temperature sensing in plants and other organisms has been the subject of numerous studies. 5-7 For many years, the activation of HSPs following a sharp temperature increase was thought to be regulated by denatured cytosolic proteins, that upon sequestering Hsp70 and Hsp90, would derepress heat shock transcription factors (HSFs), thereby inducing the upregulation of heat shock genes. [8][9][10] Yet, the overexpression of HSPs, so called the heat shock response (HSR), can be activated under mild physiological conditions that are unlikely to cause any protein denaturation in the cell. [11][12][13] Although multiple HSR triggering mechanisms may co-exist, 6,14-16 recent evidences in bacteria, algae, plants and mammalian cells point at the understanding how plants sense and respond to heat stress is central to improve crop tolerance and productivity. recent findings in Physcomitrella patens demonstrated that the controlled passage of calcium ions across the plasma membrane regulates the heat shock response (hSr). to investigate the effect of membrane lipid composition on the plant hSr, we acclimated P. patens to a slightly elevated yet physiological growth temperature and analysed the signature of calcium influx under a mild heat shock. Compared to tissues grown at 22°C, tissues grown at 32°C had significantly higher overall membrane lipid saturation level and, when submitted to a short heat shock at 35°C, displayed a noticeably reduced calcium influx and a consequent reduced heat shock gene expression. these results show that temperature differences, rather than the absolute temperature, determine the extent of the plant hSr and indicate that membrane lipid composition regulates the calcium-dependent heat-signaling pathway.

We describe the total lipid content, lipid class composition and fatty acid profiles of adult forage fishes (anchovy, sardine and sprat) sampled in the NW Mediterranean Sea in 2010 and 2011. Inter-and intra-species differences were mostly related to sampling period with limited effect of gender or total length. As an assemblage, total lipid content and relative levels of triacylglycerols and fatty acids 16:1n7, 20:5n3 and 14:0 in forage fish were highest in summer and autumn, indicating better feeding conditions and a more pronounced diatom-supported food web. In contrast, total lipid content was lowest at the end of winter and spring, and coincided with high levels of 22:6n3, indicating a more herbivorous diet based on dinoflagellates. Resource partitioning and niche separation, as inferred from fatty acid profiles, were apparent between species. Sardine showed a more diverse, temporally separated feeding strategy than anchovy, and dietary overlap was higher in winter than summer with sardine having higher markers of copepods, 22:1n11 and 20:1n9. Sprat collected in winter occupied a separate niche area to both sardine and anchovy with higher total lipid content and carnivory biomarker 18:1n9. Our results show that the lipid dynamics of forage fishes can be used to gain quantitative insights into sub-system level changes in species interactions, including prey and predator productivity.

Cellular membranes respond rapidly to various environmental perturbations. Previously we showed that modulations in membrane fluidity achieved by heat stress (HS) resulted in pronounced membrane organization alterations which could be intimately linked to the expression and cellular distribution of heat shock proteins. Here we examine heat-induced membrane changes using several visualisation methods. With Laurdan two-photon microscopy we demonstrate that, in contrast to the enhanced formation of ordered domains in surface membranes, the molecular disorder is significantly elevated within the internal membranes of cells preexposed to mild HS. These results were compared with those obtained by anisotropy, fluorescence lifetime and electron paramagnetic resonance measurements. All probes detected membrane changes upon HS. However, the structurally different probes revealed substantially distinct alterations in membrane heterogeneity. These data call attention to the careful interpretation of results obtained with only a single label. Subtle changes in membrane microstructure in the decision-making of thermal cell killing could have potential application in cancer therapy.