SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

Everything on the right place ­ the role of VPS10P receptors in intracellular protein sorting / Wszystko na swoim miejscu ­ rola receptorów VPS10P w komórkowej segregacji bialek.

VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P domain receptors have been well-described in neurons, where efficient sorting of proteins is crucial for cell viability. Dysfunctions in neuronal actions of VPS10P domain receptors are linked to disturbances in neuronal plasticity and development of neurodegenerative disorders. VPS10P domain receptors are also crucial for lipid metabolism, mainly through transport of lipolytic enzymes or influencing the uptake of lipoproteins by the cells. Emerging evidence suggests that VPS10P domain receptors can play important roles in immune response evoked by immune or glial cells. They are also key players in pathogenesis of cancers.

A robust and representative lower bound on object processing speed in humans.

How early does the brain decode object categories? Addressing this question is critical to constrain the type of neuronal architecture supporting object categorization. In this context, much effort has been devoted to estimating face processing speed. With onsets estimated from 50 to 150 ms, the timing of the first face-sensitive responses in humans remains controversial. This controversy is due partially to the susceptibility of dynamic brain measurements to filtering distortions and analysis issues. Here, using distributions of single-trial event-related potentials (ERPs), causal filtering, statistical analyses at all electrodes and time points, and effective correction for multiple comparisons, we present evidence that the earliest categorical differences start around 90 ms following stimulus presentation. These results were obtained from a representative group of 120 participants, aged 18-81, who categorized images of faces and noise textures. The results were reliable across testing days, as determined by test-retest assessment in 74 of the participants. Furthermore, a control experiment showed similar ERP onsets for contrasts involving images of houses or white noise. Face onsets did not change with age, suggesting that face sensitivity occurs within 100 ms across the adult lifespan. Finally, the simplicity of the face-texture contrast, and the dominant midline distribution of the effects, suggest the face responses were evoked by relatively simple image properties and are not face specific. Our results provide a new lower benchmark for the earliest neuronal responses to complex objects in the human visual system.

Early ERPs to faces: aging, luminance, and individual differences.

Recently, Rousselet et al. reported a 1 ms/year delay in visual processing speed in a sample of healthy aged 62 subjects (Frontiers in Psychology 2010, 1:19). Here, we replicate this finding in an independent sample of 59 subjects and investigate the contribution of optical factors (pupil size and luminance) to the age-related slowdown and to individual differences in visual processing speed. We conducted two experiments. In experiment 1 we recorded EEG from subjects aged 18-79. Subjects viewed images of faces and phase scrambled noise textures under nine luminance conditions, ranging from 0.59 to 60.8 cd/m(2). We manipulated luminance using neutral density filters. In experiment 2, 10 young subjects (age < 35) viewed similar stimuli through pinholes ranging from 1 to 5 mm. In both experiments, subjects were tested twice. We found a 1 ms/year slowdown in visual processing that was independent of luminance. Aging effects became visible around 125 ms post-stimulus and did not affect the onsets of the face-texture ERP differences. Furthermore, luminance modulated the entire ERP time-course from 60 to 500 ms. Luminance effects peaked in the N170 time window and were independent of age. Importantly, senile miosis and individual differences in pupil size did not account for aging differences and inter-subject variability in processing speed. The pinhole manipulation also failed to match the ERPs of old subjects to those of young subjects. Overall, our results strongly suggest that early ERPs to faces (<200 ms) are delayed by aging and that these delays are of cortical, rather than optical origin. Our results also demonstrate that even late ERPs to faces are modulated by low-level factors.

Early ERPs to faces and objects are driven by phase, not amplitude spectrum information: evidence from parametric, test-retest, single-subject analyses.

One major challenge in determining how the brain categorizes objects is to tease apart the contribution of low-level and high-level visual properties to behavioral and brain imaging data. So far, studies using stimuli with equated amplitude spectra have shown that the visual system relies mostly on localized information, such as edges and contours, carried by phase information. However, some researchers have argued that some event-related potentials (ERP) and blood-oxygen-level-dependent (BOLD) categorical differences could be driven by nonlocalized information contained in the amplitude spectrum. The goal of this study was to provide the first systematic quantification of the contribution of phase and amplitude spectra to early ERPs to faces and objects. We conducted two experiments in which we recorded electroencephalograms (EEG) from eight subjects, in two sessions each. In the first experiment, participants viewed images of faces and houses containing original or scrambled phase spectra combined with original, averaged, or swapped amplitude spectra. In the second experiment, we parametrically manipulated image phase and amplitude in 10% intervals. We performed a range of analyses including detailed single-subject general linear modeling of ERP data, test-retest reliability, and unique variance analyses. Our results suggest that early ERPs to faces and objects are due to phase information, with almost no contribution from the amplitude spectrum. Importantly, our results should not be used to justify uncontrolled stimuli; to the contrary, our results emphasize the need for stimulus control (including the amplitude spectrum), parametric designs, and systematic data analyses, of which we have seen far too little in ERP vision research.