Academic literature on the topic 'Alpha-secretases'

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

Tumor necrosis factor-alpha converting enzyme (TACE) is the first described and best characterized secretase. In this review the structure and the possible roles for TACE are summarized. The substrate specificity and the regulation of TACE activity as well as redundancy and possible cooperations of distinct secretases are also discussed.

Alzheimer’s disease remains a prevailing neurodegenerative condition which has an array physical, emotional, and financial consequences to patients and society. In the past decade, there has been a greater degree of investigation on therapeutic small peptides. This group of biomolecules have a profile of fundamentally sound characteristics which make them an intriguing area for drug development. Among these biomolecules, there are four modulatory mechanisms of interest in this review: alpha-, beta-, gamma-secretases, and amylin. These protease-based biomolecules all have a contributory role in the amyloid cascade hypothesis. Moreover, the involvement of various biochemical pathways intertwines these peptides to have shared regulators (i.e., retinoids). Further clinical and translational investigation must occur to gain a greater understanding of its potential application in patient care. The aim of this narrative review is to evaluate the contemporary literature on these protease biomolecule modulators and determine its utility in the treatment of Alzheimer’s disease.

AbstractAlthough Alzheimer’s disease (AD) is the most common form of dementia in the United States, development of therapeutics has proven difficult. Invertebrate alternatives to current mammalian AD models have been successfully employed to study the etiology of the molecular hallmarks of AD. The marine snail Aplysia californica offers a unique and underutilized system in which to study the physiological, behavioral, and molecular impacts of AD. Mapping of the Aplysia proteome to humans and cross-referencing with two databases of genes of interest in AD research identified 898 potential orthologs of interest in Aplysia. Included among these orthologs were alpha, beta and gamma secretases, amyloid-beta, and tau. Comparison of age-associated differential expression in Aplysia sensory neurons with that of late-onset AD in the frontal lobe identified 59 ortholog with concordant differential expression across data sets. The 21 concordantly upregulated genes suggested increased cellular stress and protein dyshomeostasis. The 47 concordantly downregulated genes included important components of diverse neuronal processes, including energy metabolism, mitochondrial homeostasis, synaptic signaling, Ca++ regulation, and cellular cargo transport. Compromised functions in these processes are known hallmarks of both human aging and AD, the ramifications of which are suggested to underpin cognitive declines in aging and neurodegenerative disease.

Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer’s disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced through cleavage of the amyloid precursor protein (APP) by the beta secretase BACE1. However, this is precluded by cleavage of APP by the non-amyloidogenic alpha secretase, ADAM10. Previous studies have found that BACE1 expression was increased in the CNS of PWH with HAND as well as animal models of HAND. Further, BACE1 contributed to neurotoxicity. Yet in in vitro models, the role of ADAM10 and its potential regulatory mechanisms had not been examined. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), a regulator of ADAM10 that is implicated in aging and in AD. Both decreases were blocked with NMDA receptor antagonists, and treatment with NMDA was sufficient to induce reduction in ADAM10 and SIRT1 protein levels. Furthermore, decreases in SIRT1 protein levels were observed at an earlier time point than the decreases in ADAM10 protein levels, and the reduction in SIRT1 was reversed by proteasome inhibitor MG132. This study indicates that HIV-associated insults, particularly excitotoxicity, contribute to changes of APP secretases by downregulating levels of ADAM10 and its regulator.

En plus d'être clivée par les β- et les γ-sécrétases lors du processus amyloïdogénique de la maladie d'Alzheimer, l'APP (Amyloid Precursor Protein) peut également subir un clivage grâce à l'α-sécrétase qui conduit à la libération des fragments d'APP soluble α (sAPPα)(voie non-amyloïdogénique) prévenant ainsi l'accumulation des peptides β-amyloïdes pathogènes. Les études sur le clivage de l'APP par l'α-sécrétase ont montré que l'activité de cette enzyme était constitutive mais aussi régulée. Lors de mon travail de thèse, nous avons montré que l'expression du récepteur de la sérotonine de type 4 (R 5-HT4) favorise la coupure constitutive de l'APP par l'α sécrétase ADAM10 et la libération des fragments non-amyloïdogéniques, sAPPα, aussi bien dans les cellules HEK-293 que dans les neurones corticaux en culture primaire. Ce mécanisme est totalement indépendant de la production d'AMPc, mais reste dépendant d'une interaction entre le R 5-HT4, l'APP et la forme mature de l'ADAM10. Le R 5-HT4, contrairement à d'autres récepteurs couplés aux protéines G (RCPG) décrits pour promouvoir la libération de sAPPα, est en effet capable d'interagir physiquement avec l'α-sécrétase ADAM10 et son substrat, l'APP. Cette interaction, directe ou indirecte, favorise l'adressage de l'ADAM10 et de l'APP à la membrane plasmique, là où la coupure en α est majoritaire. Toute rétention du R 5-HT4 à l'intérieur de la cellule retient également l'APP et l'ADAM10 sous sa forme inactive et annule la production de sAPPα. La régulation de l'α-sécrétase est toujours dépendante de l'activation du R 5-HT4 par un agoniste. Cet effet étant cette fois dépendant de la voie de signalisation de l'AMPc et de la protéine Epac comme cela avait déjà été démontré. Ces résultats décrivent pour la première fois un mécanisme par lequel un RCPG stimule le clivage constitutif de l'APP par l'α sécrétase et fournit de nouvelles perspectives pour la régulation de l'APP et le contrôle de l'adressage de l'α-sécrétase ADAM10
In addition to the amyloidogenic pathway of Alzheimer's disease whereby Amyloid Precursor Protein (APP) is cleaved by β- et γ-secretases, the substrate can also be cleaved by α secretases, producing soluble APP alpha (sAPPα)(non-amyloidogenic pathway) and thus preventing the generation of pathogenic Amyloid-beta peptides. Despite, intensive research, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. In this study, we tried to elucidate how 5-HT4Rs stimulate the release of sAPPα. We show that expression of serotonin type 4 receptors (5-HT4Rs) constitutively induces APP cleavage by the α-secretase ADAM10 and release of non-amyloidogenic fragments, sAPPα, in HEK-293 cells and cortical neurons. This effect is fully independent of cAMP production and relies on the transport of the 5-HT4R/APP/mature ADAM10 complex to the plasma membrane. Indeed, 5-HT4Rs but not other G protein-coupled receptors (GPCRs) known to activate sAPPα release, physically interact, directly or indirectly, with ADAM10 and APP to promote their targeting to the plasma membrane. Stimulation of 5 HT4Rs by an agonist further increases sAPPα fragments release and this effect is mediated through cAMP/Epac signalling. These findings describe a new mechanism whereby a GPCR stimulates the cleavage of APP by α-secretases and provide novel insights into the regulation of APP and α-secretase sorting

Dans le système nerveux central (SNC), les oligodendrocytes (OL) enveloppent les axones de leurs prolongements membranaires formant ainsi les gaines de myéline. La mort des OL et la perte de myéline (démyélinisation) surviennent dans les maladies démyélinisantes telles que la sclérose en plaques, pour lesquelles il n'existe pas de traitement efficace. Notre objectif est de stimuler des processus de réparation endogène via la voie ADAM10/sAPPa. Le fragment soluble sAPPa est un peptide neuroprotecteur issu du clivage de la protéine précurseur de l'amyloïde (APP) par les a-secrétases de la famille ADAM (A Desintegrin And Metalloprotease). Nous étudions plus particulièrement ADAM10 car il s'agit de l'a-sécrétase principale dans le SNC. Nos résultats antérieurs montrent que l'activation pharmacologique des a-sécrétases stimule la différenciation des OL in vitro, la protection de la myéline contre la démyélinisation et la remyélinisation ex vivo et in vivo et améliore la fonction locomotrice. L'objectif de ma thèse était donc d'approfondir le rôle d'ADAM10 dans les OL, dans la formation et la maintenance de la myéline. Trois objectifs ont été menés. Le premier objectif était d'étudier l'expression régionale et cellulaire d'ADAM10 dans le SNC par immunomarquage de la protéine dans le SNC de souris adultes et dans des cultures neuronales et gliales primaires. Nous avons observé une large expression de l'enzyme dans le cerveau, le cervelet et la moelle épinière, plus forte dans l'hippocampe et le cortex piriforme. Bien que l'expression d'ADAM10 soit majoritairement neuronale dans les tissus, nous avons pu détecter ADAM10 in vitro dans les OL, les astrocytes et la microglie. Le second objectif était d'étudier le rôle de l'ADAM10 oligodendrocytaire dans la myélinisation. Nous avons donc généré une nouvelle lignée de souris (KOOLA10) permettant la délétion d'ADAM10 dans les OL à des moments spécifiques du développement des OL et de la myéline. Dans cette lignée, l'exon 3 du gène Adam10 flanqué de deux séquences loxP est excisé lors de l'induction par le tamoxifène de la recombinase Cre, exprimée sous le contrôle du promoteur PLP (Proteolipid Protein). Lorsque la déficience est induite à la naissance pendant l'oligodendrogenèse, des défauts d'exploration sont observés à P21, compensés par la suite. Lorsque la déficience est induite à l'âge adulte lors de la maintenance de la myéline, ces défauts s'aggravent avec le temps. Des analyses supplémentaires sont nécessaires pour expliquer ces déficits comportementaux. De manière inattendue, les niveaux de protéine MBP (Myelin Basic Protein) ne montrent pas de changement apparent chez les KO. Le troisième objectif était d'étudier le rôle d'ADAM10 dans le développement et la fonctionnalité des OL. Les résultats de l'invalidation d'ADAM10 à l'aide de siRNA dans la lignée d'OL 158N montrent une diminution de l'expression des gènes de la myéline sans différences dans la morphologie, la prolifération ou la migration des OL. Pour valider ces résultats, nous avons mis en place un protocole d'isolement et de culture primaires d'OL. Les données préliminaires indiquent une diminution de l'expression des gènes de la myéline dans les OL issus de souris KO. Enfin, des cultures organotypiques de cervelet de souris KO montrent une diminution significative du nombre d'axones myélinisés après une démyélinisation induite par lysolécithine, suggérant un effet protecteur d'OL ADAM10 dans la protection ou la réparation de la myéline. En conclusion, j'ai établi la cartographie d'ADAM10 dans le SNC, j'ai généré la lignée de souris KOOLA10 et mis en place différents outils permettant d'étudier le rôle de l'ADAM10 oligodendrocytaire dans la myélinisation. Mes données indiquent un rôle important de l'ADAM10 dans les OL, révélant même des conséquences comportementales. Des études complémentaires sont nécessaires pour mieux comprendre le rôle de cette enzyme dans la maintenance de la myéline et la re/myélinisation du SNC
In the central nervous system (CNS), oligodendrocytes (OL) envelop the axons with their membrane extensions, forming the myelin sheath. The OL death and the loss of myelin (demyelination) occur in demyelinating diseases such as multiple sclerosis, for which there is no specific cure nowadays. Our goal is to enhance an endogenous repair process via the ADAM10/sAPPa pathway. The Amyloid Precursor Protein (APP) can be cleaved by a-secretases, members of the ADAM (A Desintegrin And Metalloprotease) family such as ADAM10, the main a-secretase in the CNS. The enzymatic cleavage of APP generates a neuroprotective soluble peptide called sAPPa. Our previous results showed that the pharmacological activation of a-secretases was able to enhance OL differentiation in vitro, to promote myelin protection from demyelination, to enhance remyelination ex vivo and in vivo and to improve the locomotor function. The aim of my thesis was, thus, to further investigate the role of oligodendroglial ADAM10 in myelin formation and maintenance. Three lines of investigation have been pursued. The first aim was to investigate the regional and cellular expression of ADAM10 in the CNS by immunolabeling of ADAM10 protein in adult mice and in primary neuronal and glial cultures. ADAM10 was widely expressed in brain, cerebellum and spinal cord with high expression in the hippocampus and piriform cortex. Neurons expressed much more ADAM10 than glial cells in CNS tissues and in vitro we were able to detect ADAM10 in neurons, OL, astrocytes and microglia. The second aim was to investigate the role of oligodendroglial ADAM10 in myelination. Therefore, we have created a novel mouse strain (KOOLA10) that allows the deletion of OL ADAM10 at specific time points related to the process of oligodendrogenesis and myelination. In this mouse strain, the deficiency is induced by the excision of the exon 3 of Adam10 gene flanked by 2 loxP sequences by the Cre recombinase, which is under the control of the PLP (Proteolipid Protein) promoter. When ADAM10 deficiency was induced at birth during oligodendrogenesis, an impairment in exploratory activity was observed at P21 but it was compensated later on. When ADAM10 deficiency was induced during myelin maintenance in adult mice, the aforementioned behavior worsened over time. Further analysis is still required to explain the behavioral changes observed in KO mice. Surprisingly, the level of MBP (Myelin Basic Protein), assessed by western blot and immunohistological studies, did not show an apparent change in KO mice. The third aim was to investigate the role of ADAM10 in OL development and functionality. The ADAM10 knock-down using siRNA in the 158N OL cell line did not modify cell morphology, proliferation or migration but it induced a decrease in myelin gene expression. To validate these results, we set up a new OL primary cell isolation and culture protocol. Preliminary results also pointed to a reduction of myelin genes expression in ADAM10-deficient OL. Finally, we used organotypic culture of cerebellum, highly rich in myelin, to address the effect of ADAM10 deficiency. We set up a transfection protocol to knock down ADAM10 in cerebellar slices and further focused on the study of myelination in KOOLA10. A significant decrease in the number of myelinated axons was observed in cerebellar slices from KO mice after demyelination, suggesting a beneficial effect of OL ADAM10 in myelin protection or repair. In conclusion, I have shown the distribution of ADAM10 in the CNS, generated the KOOLA10 mouse strain and set up different protocols and tools that allow the investigation of the role of oligodendroglial ADAM10 in myelination. I have obtained evidence suggesting that OL ADAM10 affects exploratory behavior and myelin and is necessary for myelin protection and/or repair. Further investigation is required to better decipher the role of OL ADAM10 in myelin maintenance, and CNS re/myelination

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.