13 research outputs found

    Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer's disease-like mice

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    Pathological aggregation of amyloid-ő≤ (Aő≤) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces A plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aő≤ without changes in Aő≤ plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD

    Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer's disease-like mice

    Get PDF
    Pathological aggregation of amyloid-ő≤ (Aő≤) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces A plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aő≤ without changes in Aő≤ plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD

    A SEPT1-based scaffold is required for Golgi integrity and function

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    Compartmentalization of membrane transport and signaling processes is of pivotal importance to eukaryotic cell function. While plasma membrane compartmentalization and dynamics are well known to depend on the scaffolding function of septin GTPases, the roles of septins at intracellular membranes have remained largely elusive. Here, we show that the structural and functional integrity of the Golgi depends on its association with a septin 1 (SEPT1)-based scaffold, which promotes local microtubule nucleation and positioning of the Golgi. SEPT1 function depends on the Golgi matrix protein GM130 (also known as GOLGA2) and on centrosomal proteins, including CEP170 and components of ő≥-tubulin ring complex (ő≥-Turc), to facilitate the perinuclear concentration of Golgi membranes. Accordingly, SEPT1 depletion triggers a massive fragmentation of the Golgi ribbon, thereby compromising anterograde membrane traffic at the level of the Golgi

    Single-Molecule Imaging of Recycling Synaptic Vesicles in Live Neurons

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    The capacity of neurons to communicate and store information in the brain critically depends on neurotransmission, a process which relies on the release of chemicals called neurotransmitters stored in synaptic vesicles at the presynaptic nerve terminals. Following their fusion with the presynaptic plasma membrane, synaptic vesicles are rapidly reformed via compensatory endocytosis. The investigation of the endocytic pathway dynamics is severely restricted by the diffraction limit of light and, therefore, the recycling of synaptic vesicles, which are roughly 45 nm in diameter, has been primarily studied with electrophysiology, low-resolution fluorescence-based techniques, and electron microscopy. Here, we describe a recently developed technique we named subdiffractional tracking of internalized molecules (sdTIM) that can be used to track and study the mobility of recycling synaptic vesicles in live hippocampal presynapses. The chapter provides detailed guidelines on the application of the sdTIM protocol and highlights controls, adaptations, and limitations of the technique
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