Investigating the Role of the Amyloid Precursor Protein in the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by a progressive loss of cognition. Histopathologically, AD is defined by the presence of two lesions, senile plaques (SP) and neurofibrillary tangles (NFT), which result from the accumulation and deposition of the amyloid-β peptide (Aβ) and the aggregation of hyperphosphorylated tau protein, respectively. Aβ is formed upon sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases and is secreted extracellularly. The accumulation of extracellular Aβ is thought to initiate a pathogenic cascade resulting in synaptic dysfunction in neurons, followed by the their eventual demise through apoptosis. However, while Aβ has been shown to be increased in AD patients' brains, little is known about how the cleavage of APP and the subsequent generation of Aβ is influenced or if the cleavage process changes over time. Moreover, while the effects of Aβ on neurons are known, the exact mechanism remains unclear. Many have postulated that Aβ exerts its effects by binding a putative receptor, but the search for an Aβ receptor has so far remained inconclusive. Interestingly, one of the proposed potential receptor for Aβ is APP itself. In this model, soluble oligomeric Aβ binds cell-surface APP, inducing its dimerization leading to all the downstream effects of Aβ in cells -- e.g. cell death and/or synaptic dysfunction. Moreover, it has been proposed that Aβ can promote its own production in neurons, thereby initiating a pathogenic loop. However, isolating Aβ-induced APP signaling has remained challenging due to the promiscuous nature of Aβ binding. To work around this problem, we used an antibody-mediated approach to artificially trigger the dimerization of cell-surface APP in cells. We found that dimerization of APP could recapitulate all of the effects of oligomeric Aβ in hippocampal neurons, triggering neuronal death at high concentrations and interfering with normal synaptic functions low concentrations. We also found that dimerization of APP is sufficient to promote the amyloidogenic pathway, by increasing levels of the β-secretase BACE1, resulting in increased Aβ production. Finally, we found that dimerization of APP triggered caspase-dependent cleavage of APP and the formation of a second neurotoxic fragment, termed C31, which also mimics the effects of Aβ in hippocampal neurons. Taken together, our data provides support for the occurrence of a positive pathogenic feedback loop involving Aβ, APP and C31 in neurons

The post-minig context at Decazeville-Firmi concession (Aveyron, France) : analysis of impacts resulting from the cessation of pumping at the central shaft. Survey of various scenarios related to the water level of the Pit lake in the Grande Decouverte

International audienceWithin the frame of the Survey related to the cessation of mine workings in Decazeville-Firmi concession, various impacts resulting from the cessation of pumping at the Central Shaft were assessed. Mainly these impacts are related to groundwater behaviour in the abandoned underground coalmines, hydrochemistry of waters discharged to the environment, ground stability concerns and coal gas emanations. This analysis allowed the choice of the most appropriate elevation of the pit lake level in the Grande Découverte, with the necessity to continue the pumping. Two main objectives were reached. The elected elevation is high enough to result in a permanent chemical stratification, which allows the pumping of the superficial waters and its discharge to natural watercourses without any treatment. The elected elevation is low enough to avoid any problem of inflow of water or ground stability at some particular places which might have been threatened by the rising of the piezometric level of the mining aquifer. Lastly, the elected elevation of the pit lake allows a quality scenery design around the pit lake.Dans le cadre de la constitution du Dossier d'arrêt des travaux miniers dans la concession de Decazeville-Firmi, différents impacts résultant de l'arrêt du pompage au Puits Central ont été étudiés. Ces impacts sont principalement relatifs au comportement de l'aquifère minier, à la qualité des eaux restituées au milieu naturel, à la stabilité des terrains et aux gaz de mines. Cette étude a conduit à la définition de la meilleure cote du lac minier de Decazeville dans la Grande Découverte, en respectant deux principaux objectifs, avec la nécessité de poursuivre le pompage. La cote retenue est suffisamment élevée pour permettre l'établissement d'une stratification chimique permanente dans le lac minier, ce qui rend possible le pompage par soutirage de la tranche d'eau superficielle du lac et sa restitution au milieu naturel sans traitement particulier. La cote est suffisamment basse pour éviter tout problème de venue d'eau ou de stabilité des terrains en quelques zones particulières qui auraient pu être menacées par la remontée du niveau piézométrique de l'aquifère minier. Enfin, la cote retenue permet de réaliser un aménagement paysager de qualité autour du lac minier

A detailed study of the diastereoselective catalytic hydrogenation of 6-hydroxytetrahydroisoquinoline-(3R)-carboxylic ester intermediates

A key step towards a highly-selective antagonist of ionotropic glutamate receptors entails the diastereoselective arene hydrogenation of an enantiopure tetrahydroisoquinoline. An extensive screen using parallel reactors was conducted and led to the discovery of several Pd/C catalysts giving high yield and improved diastereoselectivity from 75 : 25 to 95 : 5. A detailed kinetic study of the best system was performed and supports the reduction occuring in two-steps.

Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression

Alzheimer’s disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/ target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsyderived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

OBJECTIVE: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers

Kinetics of Eotaxin Generation and Its Relationship to Eosinophil Accumulation in Allergic Airways Disease: Analysis in a Guinea Pig Model In Vivo

Challenge of the airways of sensitized guinea pigs with aerosolized ovalbumin resulted in an early phase of microvascular protein leakage and a delayed phase of eosinophil accumulation in the airway lumen, as measured using bronchoalveolar lavage (BAL). Immunoreactive eotaxin levels rose in airway tissue and BAL fluid to a peak at 6 h falling to low levels by 12 h. Eosinophil numbers in the tissue correlated with eotaxin levels until 6 h but eosinophils persisted until the last measurement time point at 24 h. In contrast, few eosinophils appeared in BAL over the first 12 h, major trafficking through the airway epithelium occurring at 12–24 h when eotaxin levels were low. Constitutive eotaxin was present in BAL fluid. Both constitutive and allergen-induced eosinophil chemoattractant activity in BAL fluid was neutralized by an antibody to eotaxin. Allergen-induced eotaxin appeared to be mainly in airway epithelium and macrophages, as detected by immunostaining. Allergen challenge of the lung resulted in a rapid release of bone marrow eosinophils into the blood. An antibody to IL-5 suppressed bone marrow eosinophil release and lung eosinophilia, without affecting lung eotaxin levels. Thus, IL-5 and eotaxin appear to cooperate in mediating a rapid transfer of eosinophils from the bone marrow to the lung in response to allergen challenge