Nonsteroidal Anti-Inflammatory Drugs and Ectodomain Shedding of the Amyloid Precursor Protein

Background: Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). Several mechanisms have been proposed to explain these findings including increased shedding of the soluble ectodomain of the amyloid precursor protein (sAPP), which functions as a neurotrophic and neuroprotective factor in vitro and in vivo. Objective: To clarify whether NSAIDs consistently stimulate sAPP secretion. Methods: 293-EBNA cells with stable overexpression of an APP-alkaline phosphatase fusion protein (APP-AP), SH-SY5Y and PC12 cells or primary telencephalic chicken neurons were treated with ibuprofen or indomethacin. APP shedding was then determined by measuring AP activity in conditioned media, Western blot analysis with antibodies against total sAPP or specific for sAPP-alpha, or in a pulse-chase paradigm. Results: AP activity in conditioned media was not increased after NSAID treatment of 293-EBNA cells whereas it was elevated by phorbol ester. Surprisingly, ibuprofen or indomethacin treatment of SH-SY5Y and PC12 cells expressing endogenous APP did not cause changes in sAPP or sAPP-alpha secretion or downregulation of cellular APP. These findings were further corroborated in primary chicken neuronal cultures. Conclusions: Using various experimental settings, we were unable to confirm sAPP or sAPP-alpha stimulation with the NSAIDs ibuprofen and indomethacin in transfected and nontransfected cells of neuronal and nonneuronal origin. Importantly, these findings seem to rule out chronic sAPP stimulation as an alternative mechanism of NSAID action in AD. Copyright (C) 2008 S. Karger AG, Base

Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

Background: Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN) occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD). The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP), events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s) in APP that regulate its sorting to the TGN have not been characterized. Results: Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life. Conclusions: We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to the TGN or lysosomes. Significantly, the data are consistent with known interactions involving the retromer, SorLA and APP. Further, these findings add to our understanding of APP targeting and potentially contribute to our knowledge of sporadic AD pathogenesis representing putative new targets for AD therapeutic strategies

Reflection groups in hyperbolic spaces and the denominator formula for Lorentzian Kac--Moody Lie algebras

This is a continuation of our "Lecture on Kac--Moody Lie algebras of the arithmetic type" \cite{25}. We consider hyperbolic (i.e. signature $(n,1)$) integral symmetric bilinear form $S:M\times M \to {\Bbb Z}$ (i.e. hyperbolic lattice), reflection group $W\subset W(S)$, fundamental polyhedron \Cal M of $W$ and an acceptable (corresponding to twisting coefficients) set P({\Cal M})\subset M of vectors orthogonal to faces of \Cal M (simple roots). One can construct the corresponding Lorentzian Kac--Moody Lie algebra {\goth g}={\goth g}^{\prime\prime}(A(S,W,P({\Cal M}))) which is graded by $M$. We show that \goth g has good behavior of imaginary roots, its denominator formula is defined in a natural domain and has good automorphic properties if and only if \goth g has so called {\it restricted arithmetic type}. We show that every finitely generated (i.e. P({\Cal M}) is finite) algebra {\goth g}^{\prime\prime}(A(S,W_1,P({\Cal M}_1))) may be embedded to {\goth g}^{\prime\prime}(A(S,W,P({\Cal M}))) of the restricted arithmetic type. Thus, Lorentzian Kac--Moody Lie algebras of the restricted arithmetic type is a natural class to study. Lorentzian Kac--Moody Lie algebras of the restricted arithmetic type have the best automorphic properties for the denominator function if they have {\it a lattice Weyl vector $\rho$}. Lorentzian Kac--Moody Lie algebras of the restricted arithmetic type with generalized lattice Weyl vector $\rho$ are called {\it elliptic}Comment: Some corrections in Sects. 2.1, 2.2 were done. They don't reflect on results and ideas. 31 pages, no figures. AMSTe

On commensurable hyperbolic Coxeter groups

For Coxeter groups acting non-cocompactly but with finite covolume on real hyperbolic space Hn, new methods are presented to distinguish them up to (wide) commensurability. We exploit these ideas and determine the commensurability classes of all hyperbolic Coxeter groups whose fundamental polyhedra are pyramids over a product of two simplices of positive dimensions

Characterization of Contaminants from a Sanitized Milk Processing Plant

Milk processing lines offer a wide variety of microenvironments where a diversity of microorganisms can proliferate. We sampled crevices and junctions where, due to deficient reach by typical sanitizing procedures, bacteria can survive and establish biofilms. The sampling sites were the holding cell, cold storage tank, pasteurizer and storage tank - transfer pump junction. The culturable bacteria that were isolated after the sanitation procedure were predominantly Pseudomonas spp., Serratia spp, Staphylococcus sciuri and Stenotrophomonas maltophilia. We assayed several phenotypic characteristics such as the ability to secrete enzymes and siderophores, as well as the capacity of the strains to form biofilms that might contribute to their survival in a mixed species environment. The Pseudomonas spp. isolates were found to either produce proteases or lecithinases at high levels. Interestingly, protease production showed an inverse correlation with siderophore production. Furthermore, all of the Serratia spp. isolates were strong biofilm formers and spoilage enzymes producers. The organisms identified were not mere contaminants, but also producers of proteins with the potential to lower the quality and shelf-life of milk. In addition, we found that a considerable number of the Serratia and Pseudomonas spp. isolated from the pasteurizer were capable of secreting compounds with antimicrobial properties

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD

Hypocretin in cerebrospinal fluid is positively correlated with Tau and pTau

It has been suggested that sleep wake regulation as well as hypocretins play a role in the pathophysiology of Alzheimer's disease. We analyzed A beta(40), A beta(42), Tau protein, phosphorylated Tau (pTau) protein as well as hypocretin-1 concentrations in the CSF of a detection sample of 10 patients with Alzheimer's disease (AD) as well as 10 age- and gender-matched patients with major depression as a comparison group of different pathology. In order to replicate the findings, we used a confirmation sample of 17 AD patients and 8 patients with major depression. We found hypocretin-1 concentrations in CSF not to differ between patients with depression and AD. However, hypocretin-1 was significantly related to Tau (r = 0.463, p < 0.001) and pTau (r = 0.630, p < 0.0001). These effects were more pronounced in depressed patients when compared to AD patients. We conclude that hypocretin-1 may play a role in the metabolism of Tau proteins across different diagnostic entities including AD. It has to be determined whether there is a causal relationship between hypocretin-1 and Tau as well as pTau. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Guideline-adherent inpatient psychiatric psychotherapeutic treatment of behavioral and psychological symptoms of dementia. Normative definition of personnel requirements

Dementia is of increasing medical and societal relevance. Hospitalization of dementia patients is mostly due to behavioral and psychological symptoms of dementia (BPSD). There is a need for sufficient qualified personnel in hospitals in order to be able to effectively treat these symptoms. This study aims at identifying the personnel requirements for guideline-conform, evidence-based inpatient treatment concepts for patients with BPSD and to compare these with the resources defined by the German psychiatric personnel regulations (Psych-PV). Furthermore, it was the aim to identify how often patients with dementia received non-pharmacological therapy during inpatient treatment. Based on the current scientific evidence for treatment of BPSD, a schedule for a multimodal non-pharmacological treatment was defined and based on this the corresponding personnel requirements were calculated. Using the treatment indicators in psychiatry and psychosomatics (VIPP) database as a reference, it was calculated on what proportion of treatment days patients were classified into G1 according to the German Psych-PV and at least once received more than two treatment units per week. For the implementation of a guideline-oriented and evidence-based treatment plan, a higher need for personnel resources than that provided by the Psych-PV was detected in all areas. Currently patients with dementia who received at least more than two treatment units per week during inpatient hospitalization, were classified into G1 according to German Psych-PV on 17.9 % of treatment days. Despite evidence for the efficacy of non-pharmacological treatment measures on BPSD, these forms of treatment cannot be sufficiently provided under the current conditions. The realization of a new quality controlled therapeutic concept is necessary to enable optimized treatment of patients with BPSD