27 research outputs found

    Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila.

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    The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). APP can undergo two exclusive proteolytic pathways: cleavage by the α-secretase initiates the non-amyloidogenic pathway while cleavage by the β-secretase initiates the amyloidogenic pathway that leads, after a second cleavage by the γ-secretase, to amyloid-β (Aβ) peptides that can form toxic extracellular deposits, a hallmark of AD. The initial events leading to AD are still unknown. Importantly, aside from Aβ toxicity whose molecular mechanisms remain elusive, several studies have shown that APP plays a positive role in memory, raising the possibility that APP loss-of-function may participate to AD. We previously showed that APPL, the Drosophila APP ortholog, is required for associative memory in young flies. In the present report, we provide the first analysis of the amyloidogenic pathway's influence on memory in the adult. We show that transient overexpression of the β-secretase in the mushroom bodies, the center for olfactory memory, did not alter memory. In sharp contrast, β-secretase overexpression affected memory when associated with APPL partial loss-of-function. Interestingly, similar results were observed with Drosophila Aβ peptide. Because Aβ overexpression impaired memory only when combined to APPL partial loss-of-function, the data suggest that Aβ affects memory through the APPL pathway. Thus, memory is altered by two connected mechanisms-APPL loss-of-function and amyloid peptide toxicity-revealing in Drosophila a functional interaction between APPL and amyloid peptide

    Microstructural consequences of isothermal crystallization in homo- and co-polyesters based on 2,5- and 2,4-furandicarboxylic acid

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    International audienceDifferent position isomers of furandicarboxylic acid (FDCA) can be obtained from the biomass by a Henkel disproportionation reaction. 2,5- and 2,4-FDCA are obtained in amounts that are large enough to be used for the synthesis of polyethylene furanoate (PEF). The homopolyesters obtained with ethylene glycol (EG) and either 2,5- or 2,4-FDCA have a completely different crystallization behavior, for 2,5-PEF can crystallize whereas 2,4-PEF cannot, even after very long annealing times. The synthesis of random copolyesters with EG and different ratios of 2,5/2,4-FDCA may therefore allow to tune PEF crystallization ability. The partial replacement of 2,5-FDCA by its position isomer could help disrupting crystallinity analogously to what happens when EG is partially replaced by cyclohexane dimethanol (CHDM) in glycolyzed polyethylene terephthalate (PETg). This work investigates the thermal behavior of the homopolyester 2,5-PEF and the microstructural consequences of copolymerization (replacement of small amounts of 2,5-FDCA with 2,4-FDCA). Crystallization is performed in isothermal conditions after cooling down from the molten state, and investigated with both conventional DSC and Fast Scanning Calorimetry (FSC). When the amount of 2,4-FDCA-based repeating units is low (10 and 15 mol %), crystallization still occurs but with an increased induction time. Neither the crystalline nor the rigid amorphous fractions are significantly affected by copolymerization. Due to multiple and complex microstructural reorganizations observed at relatively slow heating rates, conventional DSC is inaccurate and does not provide a reliable microstructural depiction of these polyesters. The use of FSC is recommended, for it allows to obtain a better characterization of the quality and thermal stability of the formed crystals

    Molecular Mobility in Amorphous Biobased Poly(ethylene 2,5-furandicarboxylate) and Poly(ethylene 2,4-furandicarboxylate)

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    Among all the emergent biobased polymers, poly(ethylene 2,5-furandicarboxylate) (2,5-PEF) seems to be particularly interesting for packaging applications. This work is focused on the investigation of the relaxation dynamics and the macromolecular mobility in totally amorphous 2,5-PEF as well as in the less studied poly(ethylene 2,4-furandicarboxylate) (2,4-PEF). Both biopolymers were investigated by differential scanning calorimetry and dielectric relaxation spectroscopy in a large range of temperatures and frequencies. The main parameters describing the relaxation dynamics and the molecular mobility in 2,5-PEF and 2,4-PEF, such as the glass transition temperature, the temperature dependence of the α and β relaxation times, the fragility index, and the apparent activation energy of the secondary relaxation, were determined and discussed. 2,5-PEF showed a higher value of the dielectric strength as compared to 2,4-PEF and other well-known polyesters, such as poly(ethylene terephthalate), which was confirmed by molecular dynamics simulations. According to the Angell's classification of glass-forming liquids, amorphous PEFs behave as stronger glass-formers in comparison with other polyesters, which may be correlated to the packing efficiency of the macromolecular chains and therefore to the free volume and the barrier properties.</p

    dBACE overexpression in adult MB does not alter memory.

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    <p>Flies were fed with RU for 48 h before conditioning to induce <i>UAS-dBACE</i> transgene expression. STM assessed 2 h after one training session is not affected. The score of <i>MBSw</i>/<i>dBACE</i> flies is not different from that of the genetic control groups (<i>F</i><sub>(2,77)</sub> = 4.048, *<i>p</i> = 0.0214, <i>n</i> ≥ 24, Newman–Keuls <i>post-hoc</i>, <i>MBSw</i>/<i>dBACE</i> vs +/<i>dBACE p</i> > 0.05, <i>MBSw</i>/<i>dBACE</i> vs <i>MBSw</i>/+ <i>p</i> > 0.05). Bars, Mean ± SEM. PI, Performance index.</p

    dBACE overexpression exacerbates the memory deficit caused by APPL partial loss-of-function.

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    <p>Unless indicated (A, w/o RU), flies were fed with RU for 48 h. (A) Flies were submitted to one cycle training and tested 2 h later. <i>Appl</i><sup><i>d</i></sup><i>/+;MBSw/+</i> flies show an STM deficit (<i>F</i><sub>(4,101)</sub> = 11.99, ***<i>p</i> < 0.0001, <i>n</i> ≥ 14, Newman-Keuls <i>post-hoc</i>, <i>Appl</i><sup><i>d</i></sup><i>/+;MBSw/+</i> vs <i>+</i> *<i>p</i> < 0.05), and <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>dBACE</i> flies exhibit a STM score significantly lower than the genetic controls (Newman-Keuls <i>post-hoc</i>, <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>dBACE</i> vs <i>Appl</i><sup><i>d</i></sup><i>/+;MBSw/+ ***p <</i> 0.001, <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>dBACE</i> vs <i>+</i>/<i>dBACE ***p <</i> 0.001). <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>dBACE</i> flies not fed with RU (w/o RU) display a STM score significantly different from flies of the same genotype fed with RU (Newman-Keuls <i>post-hoc</i>, *<i>p</i> < 0.05), and similar to <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>+</i> flies (Newman-Keuls <i>post-hoc</i>, <i>p</i> > 0.05). (B) Learning is not affected. To assess learning, flies were tested immediately after one cycle training (<i>F</i><sub>(2,27)</sub> = 0.8522, <i>p</i> = 0.4385, <i>n</i> ≥ 8). (C) Neither shock reactivity (<i>F</i><sub>(2,21)</sub> = 2.747, <i>p</i> = 0.0896, <i>n</i> ≥ 7) nor olfactory acuity (octanol, <i>F</i><sub>(2,46)</sub> = 0.3490, <i>p</i> = 0.7073, <i>n</i> ≥ 15; methylcyclohexanol, <i>F</i><sub>(2,52)</sub> = 2.959, <i>p</i> = 0.0610, <i>n</i> ≥ 17) is impaired. Bars, Mean ± SEM. PI, Performance index. (D, E) Analysis of <i>dBACE</i> and <i>Appl</i> transcription. Total RNA was extracted from <i>MBSw</i>/<i>dBACE</i>, <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/+ and <i>Appl</i><sup><i>d</i></sup>/+;<i>MBSw</i>/<i>dBACE</i> heads. Resulting cDNA was quantified using tubulin (Tub) expression as a reference. Results shown are ratios to the reference. (D) Quantification of <i>dBACE</i> mRNA level (<i>t</i> test, <i>p</i> = 0.8376, <i>n</i> = 4). (E) Quantification of <i>Appl</i> mRNA level (<i>t</i> test, <i>p</i> = 0.2330, <i>n</i> = 3). Bars, Mean ± SEM. ns, not significant.</p
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