Risk factor SORL1: from genetic association to functional validation in Alzheimer's disease

Alzheimer's disease (AD) represents one of the most dramatic threats to healthy aging and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein to amyloid-{beta} peptides (A{beta}), and how accelerated accumulation of neurotoxic A{beta} peptides underlies neuronal cell death in rare familial but also common sporadic forms of this disease. Out of a plethora of proposed modulators of amyloidogenic processing, one protein emerged as a key factor in AD pathology, a neuronal sorting receptor termed SORLA. Independent approaches using human genetics, clinical pathology, or exploratory studies in animal models all converge on this receptor that is now considered a central player in AD-related processes by many. This review will provide a comprehensive overview of the evidence implicating SORLA-mediated protein sorting in neurodegenerative processes, and how receptor gene variants in the human population impair functional receptor expression in sporadic but possibly also in autosomal-dominant forms of AD

Comparison of luminance based metrics in different lighting conditions

In this study, we evaluate established and newly developed metrics for predicting glare using data from three different research studies. The evaluation covers two different targets: 1. How well the user’s perception of glare magnitude correlates to the prediction of the glare metrics? 2. How well do the glare metrics describe the subjects’ disturbance by glare? We applied Spearman correlations, logistic regressions and an accuracy evaluation, based on an ROC- analysis. The results show that five of the twelve investigated metrics are failing at least one of the statistical tests. The other seven metrics CGI, modified DGI, DGP, Ev, average Luminance of the image Lavg, UGP and UGR are passing all statistical tests. DGP, CGI, DGI mod and UGP have largest AUC and might be slightly more robust. The accuracy of the predictions of afore mentioned seven metrics for the disturbance by glare lies in the range of 75-83% and does not confirm findings from other studies stating a poor performance of existing glare metrics

Uncovering the high prevalence of bacterial burden in surgical site wounds with point‐of‐care fluorescence imaging

Detection of bacterial burden within or near surgical wounds is critical to reducing the occurrence of surgical site infection (SSI). A distinct lack of reliable methods to identify postoperative bioburden has forced reliance on clinical signs and symptoms of infection (CSS). As a result, infection management has been reactive, rather than proactive. Fluorescence imaging of bacterial burden (FL) is positioned to potentially flip that paradigm. This post hoc analysis evaluated 58 imaged and biopsied surgical site wounds from the multi-centre fluorescence imaging assessment and guidance clinical trial. Diagnostic accuracy measures of CSS and FL were evaluated. A reader study investigated the impact of advanced image interpretation experience on imaging sensitivity. Forty-four of fifty-eight surgical site wounds (75.8%) had bacterial loads >104 CFU/g (median = 3.11 × 105 CFU/g); however, only 3 of 44 were CSS positive (sensitivity of 6.8%). FL improved sensitivity of bacterial detection by 5.7-fold compared with CSS alone (P = .0005). Sensitivity improved by 11.3-fold over CSS among clinicians highly experienced with FL interpretation (P < .0001). Surgical sites that reach the stage of referral to a wound specialist frequently harbour asymptomatic high bacterial loads that delay healing and increase infection risk. Advanced imaging of pathological bacterial burden improves surgical site monitoring and may reduce the rate of SSIs

Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids

Vacuolar protein sorting 10 protein (VPS10P) domain receptors are a unique class of intracellular sorting receptors that emerge as major risk factors associated with psychiatric and neurodegenerative diseases, including bipolar disorders, autism, schizophrenia, as well as Alzheimer’s disease and frontotemporal dementia. Yet, the lack of suitable experimental models to study receptor functions in the human brain has hampered elucidation of receptor actions in brain disease. Here, we have adapted protocols using human cerebral organoids to the detailed characterization of VPS10P domain receptor expression during neural development and differentiation, including single-cell RNA sequencing. Our studies uncovered spatial and temporal patterns of expression unique to individual receptor species in the human brain. While SORL1 expression is abundant in stem cells and SORCS1 peaks in neural progenitors at onset of neurogenesis, SORT1 and SORCS2 show increasing expression with maturation of neuronal and non-neuronal cell types, arguing for distinct functions in development versus the adult brain. In neurons, subcellular localization also distinguishes between types of receptor species, either mainly localized to the cell soma (SORL1 and SORT1) or also to neuronal projections (SORCS1 and SORCS2), suggesting divergent functions in protein sorting between Golgi and the endo-lysosomal system or along axonal and dendritic tracks. Taken together, our findings provide an important resource on temporal, spatial, and subcellular patterns of VPS10P domain receptor expression in cerebral organoids for further elucidation of receptor (dys) functions causative of behavioral and cognitive defects of the human brain

Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: Evidence for a proximal role in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in approximately 2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of beta-amyloid (Abeta), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Abeta in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1DeltaE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Abeta levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into alpha-, beta-, and gamma-secretase derived metabolites. We propose that LR11 regulates APP processing and Abeta accumulation in vivo and is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer's disease susceptibility in humans

Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD

Resonance peak in underdoped cuprates

The magnetic susceptibility measured in neutron scattering experiments in underdoped YBa$_2$Cu$_3$O$_{7-y}$ is interpreted based on the self-consistent solution of the t-J model of a Cu-O plane. The calculations reproduce correctly the frequency and momentum dependencies of the susceptibility and its variation with doping and temperature in the normal and superconducting states. This allows us to interpret the maximum in the frequency dependence -- the resonance peak -- as a manifestation of the excitation branch of localized Cu spins and to relate the frequency of the maximum to the size of the spin gap. The low-frequency shoulder well resolved in the susceptibility of superconducting crystals is connected with a pronounced maximum in the damping of the spin excitations. This maximum is caused by intense quasiparticle peaks in the hole spectral function for momenta near the Fermi surface and by the nesting.Comment: 9 pages, 6 figure

Investigating the DSM-5 and the ICD-11 PTSD symptoms using network analysis across two distinct samples

Objective: Posttraumatic stress disorder (PTSD) has long been debated with a recent focus on the consequences of having two different diagnostic descriptions of PTSD (i.e., the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition [DSM-5] and the International Classification of Diseases-11th Edition [ICD-11]). Research has modeled PTSD as a network of interacting symptoms according to both diagnostic systems, but the relations between the two systems remain unclear regarding which symptoms are more central or interconnected. To answer this question, the present study is the first study to investigate the combined network structure of PTSD symptoms according to both systems using validated measurements (i.e., the International Trauma Questionnaire [ITQ] and the Posttraumatic Stress Disorder Checklist 5 [PCL-5] across two distinct trauma samples [a community sample, N = 2,367], and a military sample, N = 657). Method: We estimated two Gaussian Graphical Models of the combined ICD-11 and DSM-5 PTSD symptoms across the two samples. Results: Five of the six most central symptoms were the same across both samples. Conclusions: The results underline that a combination of five symptoms representing both diagnostic systems may hold central positions and potentially be important for treatment. However, the implications depend on if the different diagnostic descriptions can be reconciled in an indexical rather than constitutive perspective.Clinical Impact Statement Five identical posttraumatic stress disorder (PTSD) symptoms representing both diagnostic systems were identified across two distinct trauma exposed samples using network analysis. These symptoms may hold important positions compared with the remaining symptoms of the network and potentially be central for treatment. However, the implications depend on whether the results can be reconciled by viewing the two diagnostic descriptions of PTSD as indexical.Stress and Psychopatholog

Peatland pools are tightly coupled to the contemporary carbon cycle

Peatlands are globally important stores of soil carbon (C) formed over millennial timescales but are at risk of destabilization by human and climate disturbance. Pools are ubiquitous features of many peatlands and can contain very high concentrations of C mobilized in dissolved and particulate organic form and as the greenhouses gases carbon dioxide (CO2) and methane (CH4). The radiocarbon content (14C) of these aquatic C forms tells us whether pool C is generated by contemporary primary production or from destabilized C released from deep peat layers where it was previously stored for millennia. We present novel 14C and stable C (δ13C) isotope data from 97 aquatic samples across six peatland pool locations in the United Kingdom with a focus on dissolved and particulate organic C and dissolved CO2. Our observations cover two distinct pool types: natural peatland pools and those formed by ditch blocking efforts to rewet peatlands (restoration pools). The pools were dominated by contemporary C, with the majority of C (~50%–75%) in all forms being younger than 300 years old. Both pool types readily transform and decompose organic C in the water column and emit CO2 to the atmosphere, though mixing with the atmosphere and subsequent CO2 emissions was more evident in natural pools. Our results show little evidence of destabilization of deep, old C in natural or restoration pools, despite the presence of substantial millennial-aged C in the surrounding peat. One possible exception is CH4 ebullition (bubbling), with our observations showing that millennial-aged C can be emitted from peatland pools via this pathway. Our results suggest that restoration pools formed by ditch blocking are effective at preventing the release of deep, old C from rewetted peatlands via aquatic export

Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme

sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid-beta peptide (Abeta) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a beta-site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted Abeta levels when BACE was overexpressed, suggesting that sorLA influences beta-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA-APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-APP complex formation. To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE-APP interactions in cells. We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP