SAP97-mediated local trafficking is altered in Alzheimer disease patients' hippocampus

Synapse-asssociated protein-97 (SAP97) is responsible for the trafficking of both glutamate receptor subunits, GluR1 and NR2A, and \u3b1-secretase ADAM10 to the synaptic membrane. Here we evaluate the trafficking capability of SAP97 in Alzheimer disease (AD) patients' brain. We analyzed autoptic hippocampus and superior frontal gyrus, respectively as an affected and a less affected area, from 6 AD patients (Braak 4) and 6 healthy controls. In hippocampus, but not in superior frontal gyrus, of AD patients, ADAM10 and GluR1 synaptic membrane levels are altered while NR2A localization is not affected. Both immunoprecipitation and pull-down assays demonstrated that SAP97 failed to correctly couple to ADAM10 and GluR1, but not to NR2A. These findings not only indicate SAP97 as a point of convergence between amyloid cascade and synaptic failure in AD, but also allow a different interpretation of AD which can be now perceived as synaptic trafficking defect patholog

Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases

Interleukin (IL)-1beta is a proinflammatory cytokine implicated in various pathophysiological conditions of the CNS involving NMDA receptor activation. Circumstantial evidence suggests that IL-1beta and NMDA receptors can functionally interact. Using primary cultures of rat hippocampal neurons, we investigated whether IL-1beta affects NMDA receptor function(s) by studying (1) NMDA receptor-induced [Ca2+]i increase and (2) NMDA-mediated neurotoxicity. IL1beta (0.01-0.1 ng/ml) dose-dependently enhances NMDA-induced [Ca2+]i increases with a maximal effect of approximately 45%. This effect occurred only when neurons were pretreated with IL-1beta, whereas it was absent if IL-1beta and NMDA were applied simultaneously, and it was abolished by IL-1 receptor antagonist (50 ng/ml). Facilitation of NMDA-induced [Ca2+]i increase by IL-1beta was prevented by both lavendustin (LAV) A (500 nm) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (1 microm), suggesting an involvement of tyrosine kinases. Increased tyrosine phosphorylation of NMDA receptor subunits 2A and 2B and coimmunoprecipitation of activated Src tyrosine kinase with these subunits was observed after exposure of hippocampal neurons to 0.05 ng/ml IL-1beta. Finally, 0.05 ng/ml IL-1beta increased by approximately 30% neuronal cell death induced by NMDA, and this effect was blocked by both lavendustin A and PP2. These data suggest that IL-1beta increases NMDA receptor function through activation of tyrosine kinases and subsequent NR2A/B subunit phosphorylation. These effects may contribute to glutamate-mediated neurodegeneration

Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

Purpose: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of N- methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders. Methods: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants. Results: Four cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3AThr450Ser variant in neurons affected dendritic spine morphology. Conclusion: Overall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder

Perceived Surface Slant Is Systematically Biased in the Actively-Generated Optic Flow

Humans make systematic errors in the 3D interpretation of the optic flow in both passive and active vision. These systematic distortions can be predicted by a biologically-inspired model which disregards self-motion information resulting from head movements (Caudek, Fantoni, & Domini 2011). Here, we tested two predictions of this model: (1) A plane that is stationary in an earth-fixed reference frame will be perceived as changing its slant if the movement of the observer's head causes a variation of the optic flow; (2) a surface that rotates in an earth-fixed reference frame will be perceived to be stationary, if the surface rotation is appropriately yoked to the head movement so as to generate a variation of the surface slant but not of the optic flow. Both predictions were corroborated by two experiments in which observers judged the perceived slant of a random-dot planar surface during egomotion. We found qualitatively similar biases for monocular and binocular viewing of the simulated surfaces, although, in principle, the simultaneous presence of disparity and motion cues allows for a veridical recovery of surface slant

The economic burden of mental disorders in China, 2005–2013: implications for health policy

BACKGROUND: Mental disorders represent a major contributor to disease burden worldwide. We sought to quantify the national economic burden of mental disorders in China. METHODS: We used a prevalence-based, bottom-up approach to estimate the economic costs of mental disorders in 2005–2013 in China. Prevalence data were derived from a national survey. Cost data were derived from the electronic health records of two psychiatric hospitals that consisted of 25,289 outpatients (10 %) and inpatients (90 %) who were diagnosed with a mental disorder. Cost items included direct medical costs, direct non-medical costs, and indirect costs. RESULTS: The total annual costs of mental disorders in China increased from $1,094.8 in 2005 to$3,665.4 in 2013 for individual patients, and from $21.0 billion to$88.8 billion for the whole society. The total costs of mental disorders in 2013 accounted for more than 15 % of the total health expenditure in China, and 1.1 % of China’s gross domestic product. If the needs of the professional care for all patients with mental illnesses were fully met, the potential economic costs would have been almost five times higher than the actual estimated costs. CONCLUSIONS: Mental disorders imposed a huge economic burden on individuals and the society in China. A nation-wide strategic action plan for preventing mental disorders and promoting mental health and well-being is in urgent need to reduce the individual and societal costs of mental illnesses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12888-016-0839-0) contains supplementary material, which is available to authorized users

Development of an iterative coupled MCNP and ABAQUS heat transfer analysis process for moderated low-enriched uranium kilowatt-class space nuclear reactors

Includes bibliographical references.2024 Summer.This thesis presents the development of a coupled MCNP and ABAQUS iterative heat transfer process using unstructured meshes. The reactor cores used in this process are representative of a lowly enriched uranium Kilowatt-style reactor derived from the highly enriched uranium fueled Kilowatt Reactor Using Stirring Engine TechnologY (KRUSTY). The project considered three core fuel geometries - discs, helices, and spheres. Coreform CUBIT constructs the core geometry with is meshed in ABAQUS and read into MCNP. After the MCNP neutronics analysis, ABAQUS performs a core heat transfer analysis to calculate the temperatures in the core using the nodal energy deposition tallies from MCNP. These temperatures are binned into equally spaced temperature groups to redefine the materials in MCNP based by updating the unstructured mesh input file. The process temperature binning process was successfully completed on a single part system, however failed on a multi-part system. The complete iterative process was completed on a multi-part system, but instead the average fuel temperature and average moderator temperature were updated in MCNP after each iteration

New targets for pharmacological intervention in the glutamatergic synapse

Excitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders

Predicting Alzheimer dementia in mild cognitive impairment patients. Are biomarkers useful?

A correct clinical diagnosis in the early stage of Alzheimer disease is not only of importance given the current available treatment with acetylcholine esterase inhibitors, but would be the basis for disease-modifying therapy slowing down or arresting the degenerative process. Moreover, in the last years, several efforts have been made to determine if a patient with mild cognitive impairment has incipient Alzheimer disease, i.e. will progress to Alzheimer disease with dementia, or have a benign form of mild cognitive impairment. In this review, the recent published reports regarding progress in early and preclinical Alzheimer disease diagnosis are discussed and the role of peripheral and cerebrospinal fluid biomarkers highlighted. Approaches combining panels of different biomarkers show promise for discovering profiles that are characteristic of Alzheimer disease, even in the pre-symptomatic stage. More work is needed but available novel perspectives offered by recent introduced technologies shed some lights in identifying incipient Alzheimer disease in mild cognitive impairment subjects