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Alzheimer Disease: HELP
Articles by Monica di Luca
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, M. Di Luca wrote the following 18 articles about Alzheimer Disease.
 
+ Citations + Abstracts
1 Editorial Alzheimer's disease and modern lifestyle: what is the role of stress? 2015

Marcello, Elena / Gardoni, Fabrizio / Di Luca, Monica. ·Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. ·J Neurochem · Pubmed #26206000.

ABSTRACT: This Editorial highlights a study by Baglietto-Vargas et al. 2015 published in this issue of J. Neurochem. Stress is one of the environmental factors that can contribute to Alzheimer's disease pathogenesis. However, the role of modern-life stress has not been investigated yet. The authors reveal that modern-life stress reduces the number of dendritic spines in the hippocampus of Alzheimer's disease transgenic mice. The mechanism underlying such effect involves an increase in corticotropin-releasing hormone (CRH) release that stimulates the amyloid precursor protein (APP) processing and fosters the generation of Amyloid-β, which negatively affects dendritic spines.

2 Review ADAM10 in Alzheimer's disease: Pharmacological modulation by natural compounds and its role as a peripheral marker. 2019

Manzine, Patricia Regina / Ettcheto, Miren / Cano, Amanda / Busquets, Oriol / Marcello, Elena / Pelucchi, Silvia / Di Luca, Monica / Endres, Kristina / Olloquequi, Jordi / Camins, Antoni / Cominetti, Márcia Regina. ·Department of Gerontology, Federal University of São Carlos, São Carlos, Brazil; Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències del'Alimentació, Universitat de Barcelona, Barcelona, Spain. Electronic address: patricia_manzine@yahoo.com.br. · Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències del'Alimentació, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain. · Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institute of Nanoscience and Nanotechnology (IN2UB), Barcelona, Spain. · Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy. · Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy; Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy. · Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz, Mainz, Germany. · Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile. Electronic address: jolloquequi@gmail.com. · Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències del'Alimentació, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain. · Department of Gerontology, Federal University of São Carlos, São Carlos, Brazil. ·Biomed Pharmacother · Pubmed #30836275.

ABSTRACT: Alzheimer's disease (AD) represents a global burden in the economics of healthcare systems. Amyloid-β (Aβ) peptides are formed by amyloid-β precursor protein (AβPP) cleavage, which can be processed by two pathways. The cleavage by the α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) releases the soluble portion (sAβPPα) and prevents senile plaques. This pathway remains largely unknown and ignored, mainly regarding pharmacological approaches that may act via different signaling cascades and thus stimulate non-amyloidogenic cleavage through ADAM10. This review emphasizes the effects of natural compounds on ADAM10 modulation, which eventuates in a neuroprotective mechanism. Moreover, ADAM10 as an AD biomarker is revised. New treatments and preventive interventions targeting ADAM10 regulation for AD are necessary, considering the wide variety of ADAM10 substrates.

3 Review Synapse-to-nucleus communication: from developmental disorders to Alzheimer's disease. 2018

Marcello, Elena / Di Luca, Monica / Gardoni, Fabrizio. ·Department of Pharmacological and Biomolecular Sciences, University of Milano, Milan, Italy. · Department of Pharmacological and Biomolecular Sciences, University of Milano, Milan, Italy. Electronic address: monica.diluca@unimi.it. ·Curr Opin Neurobiol · Pubmed #29316492.

ABSTRACT: In the last decade several synaptonuclear protein messengers including Jacob, CRTC1, AIDA-1, ProSaP2/Shank3 and RNF10 have been identified and characterized as key players for modulation of synaptic transmission and synaptic plasticity. Activation of excitatory glutamatergic synapses leads to their shuttling from the synapse to the nucleus, mostly importin-mediated, and subsequent regulation of gene transcription needed for long lasting modifications of synaptic function. Accordingly, increasing evidences show that alterations of the activity of synaptonuclear messengers are correlated to synaptic failure as observed in different synaptopathies. Specifically, recent studies demonstrate that the modulation of the activity of synaptonuclear messengers could represent a novel molecular target in the pathogenesis of both neurodevelopmental disorders and neurodegenerative diseases such as Alzheimer's disease.

4 Review ADAM10 as a therapeutic target for brain diseases: from developmental disorders to Alzheimer's disease. 2017

Marcello, Elena / Borroni, Barbara / Pelucchi, Silvia / Gardoni, Fabrizio / Di Luca, Monica. ·a Department of Pharmacological and Biomolecular Sciences , Università degli Studi di Milano , Milan , Italy. · b Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences , University of Brescia , Brescia , Italy. · c Department of Neurosciences, Psychology, Drug Research, and Child Health , University of Florence , Florence , Italy. ·Expert Opin Ther Targets · Pubmed #28960088.

ABSTRACT: INTRODUCTION: In the central nervous system a disintegrin and metalloproteinase 10 (ADAM10) controls several functions such as neurodevelopment, synaptic plasticity and dendritic spine morphology thanks to its activity towards a high number of substrates, including the synaptic cell adhesion molecules as the Amyloid Precursor Protein, N-cadherin, Notch and Ephrins. In particular, ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's Disease. Areas covered: We describe the most recent discoveries in understanding of the role of ADAM10 activity at the glutamatergic excitatory synapse and its involvement in the onset of neurodevelopmental and neurodegenerative disorders. Expert opinion: A progress in the understanding of the molecular mechanisms driving ADAM10 activity at synapses and its alterations in brain disorders is the first step before designing a specific drug able to modulate ADAM10 activity.

5 Review ADAM10 in synaptic physiology and pathology. 2014

Musardo, Stefano / Marcello, Elena / Gardoni, Fabrizio / Di Luca, Monica. ·Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. ·Neurodegener Dis · Pubmed #24008925.

ABSTRACT: BACKGROUND: Generation of amyloid-β peptide is at the beginning of a cascade that leads to Alzheimer's disease. Amyloid precursor protein (APP) as well as β- and γ-secretases are the principal players involved in amyloid-β (Aβ) production, while α-secretase cleavage on APP prevents Aβ deposition. A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to act as α-secretase in neurons. OBJECTIVE: Although localization of ADAM10 in the synaptic membrane is the key for its shedding activity, currently, very little is known about the mechanisms that control the synaptic abundance of ADAM10. RESULTS: Two established forms of long-term activity-dependent plasticity, i.e., long-term potentiation and long-term depression (LTD), differentially regulate the synaptic availability and activity of ADAM10. Long-term potentiation decreases ADAM10 surface levels and activity by promoting its endocytosis. This process is mediated by activity-regulated association of ADAM10 with the clathrin adaptor protein 2 (AP2) complex. Conversely, LTD fosters ADAM10 insertion in the membrane and stimulates its activity. Furthermore, ADAM10 interaction with synapse-associated protein 97 (SAP97) is necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced spine morphology changes. CONCLUSIONS: Regulated interaction of ADAM10 with SAP97 and AP2 discloses a novel physiological mechanism of ADAM10 activity regulation at the synapses. This phenomenon produces a situation whereby synaptically regulated ADAM10 activity is positioned to modulate synaptic functioning.

6 Review Synaptic dysfunction in Alzheimer's disease. 2012

Marcello, Elena / Epis, Roberta / Saraceno, Claudia / Di Luca, Monica. ·Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. elena.marcello@unimi.it ·Adv Exp Med Biol · Pubmed #22351073.

ABSTRACT: Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. Recent studies suggested that soluble assembly states of Aβ peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aβ assemblies in causing synaptic dysfunction and cognitive deficits. Several Aβ oligomers targets and cellular mechanisms responsible of Aβ-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aβ which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aβ has a normal physiological role. On the one hand, insufficient Aβ could lead to a loss of normal function, whereas excess Aβ may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of Aβ remains to be fully understood and would certainly represent one of the main challenges to future AD research.

7 Review Alpha, beta-and gamma-secretases in Alzheimer's disease. 2012

Epis, Roberta / Marcello, Elena / Gardoni, Fabrizio / Di Luca, Monica. ·Universita degli Studi di Milano, Department of Pharmacological Sciences, Milano, Italy. ·Front Biosci (Schol Ed) · Pubmed #22202113.

ABSTRACT: Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.

8 Article Proximity ligation assay reveals both pre- and postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain. 2020

Lundgren, Jolanta L / Vandermeulen, Lina / Sandebring-Matton, Anna / Ahmed, Saheeb / Winblad, Bengt / Di Luca, Monica / Tjernberg, Lars O / Marcello, Elena / Frykman, Susanne. ·Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden. · Department of Pharmacological and Biomolecular Sciences, Universitá Degli Studi Di Milano, Milan, Italy. · Department of Diagnostic and Interventional Radiology, University Medical Center, Göttingen, Germany. · Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden. susanne.frykman@ki.se. ·BMC Neurosci · Pubmed #32019490.

ABSTRACT: BACKGROUND: Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons. RESULTS: Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density. CONCLUSIONS: We show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.

9 Article Amyloid-β Oligomers Regulate ADAM10 Synaptic Localization Through Aberrant Plasticity Phenomena. 2019

Marcello, Elena / Musardo, Stefano / Vandermeulen, Lina / Pelucchi, Silvia / Gardoni, Fabrizio / Santo, Nadia / Antonucci, Flavia / Di Luca, Monica. ·Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. elena.marcello@unimi.it. · Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. · Department of Basic Neuroscience, University of Geneva, Rue Michel-Servet 1, 1206, Geneva, Switzerland. · Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy. · Department of Life Sciences, Università degli Studi di Milano, Milan, Italy. · Department of Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy. · Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. monica.diluca@unimi.it. ·Mol Neurobiol · Pubmed #30989630.

ABSTRACT: A disintegrin and metalloproteinase 10 (ADAM10) is a synaptic enzyme that has been previously shown to limit amyloid-β

10 Article microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. 2018

Manzine, Patricia R / Pelucchi, Silvia / Horst, Maria A / Vale, Francisco A C / Pavarini, Sofia C I / Audano, Matteo / Mitro, Nico / Di Luca, Monica / Marcello, Elena / Cominetti, Márcia R. ·Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil. · Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. · Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, Università di Firenze, Florence, Italy. · Faculty of Nutrition, Federal University of Goiás, Goiânia, MG, Brazil. · Department of Medicine, Federal University of São Carlos, São Carlos, SP, Brazil. ·J Alzheimers Dis · Pubmed #29036829.

ABSTRACT: ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.

11 Article Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity. 2016

Zussy, Charleine / Loustalot, Fabien / Junyent, Felix / Gardoni, Fabrizio / Bories, Cyril / Valero, Jorge / Desarménien, Michel G / Bernex, Florence / Henaff, Daniel / Bayo-Puxan, Neus / Chen, Jin-Wen / Lonjon, Nicolas / de Koninck, Yves / Malva, João O / Bergelson, Jeffrey M / di Luca, Monica / Schiavo, Giampietro / Salinas, Sara / Kremer, Eric J. ·Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique 5535, 34293 Montpellier, France, Université de Montpellier, 34000 Montpellier, France. · Università degli Studi di Milano, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, 20122 Milan, Italy. · Mental Health Institute of Quebec and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec City, G1V 0A6 Quebec, Canada. · Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. · Université de Montpellier, 34000 Montpellier, France, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Inserm, 34394 Montpellier, France. · Institut Régional du Cancer Montpellier, Inserm, 34090 Montpellier, France. · Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. · Département de Neurochirurgie, Hôpital Gui de Chauliac, 34000 Montpellier, France. · Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom, and. · Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique 5535, 34293 Montpellier, France, Université de Montpellier, 34000 Montpellier, France, sara.salinas@inserm.fr eric.kremer@igmm.cnrs.fr. ·J Neurosci · Pubmed #27629708.

ABSTRACT: SIGNIFICANCE STATEMENT: This study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.

12 Article The soluble extracellular fragment of neuroligin-1 targets Aβ oligomers to the postsynaptic region of excitatory synapses. 2015

Dinamarca, Margarita C / Di Luca, Monica / Godoy, Juan A / Inestrosa, Nibaldo C. ·Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile. · Department of Pharmacological Sciences, University of Milan, Milan, Italy. · Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile; Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. Electronic address: ninestrosa@bio.puc.cl. ·Biochem Biophys Res Commun · Pubmed #26325471.

ABSTRACT: Amyloid-β oligomers (Aβo) play a major role in the synaptic dysfunction of Alzheimer's disease (AD). Neuroligins are postsynaptic cell-adhesion molecules, that share an extracellular domain with high degree of similarity to acetylcholinesterase (AChE), one of the first putative Aβo receptors. We recently found that Aβo interact with the soluble N-terminal fragment of neuroligin-1 (NL-1). We report here that Aβo associate with NL-1 at excitatory hippocampal synapses, whereas almost no association was observed with neuroligin-2, an isoform present at inhibitory synapses. Studies using purified hippocampal postsynaptic densities indicate that NL-1 interacts with Aβo in a complex with GluN2B-containing NMDA receptors. Additionally, the soluble fragment of NL-1 was used as a scavenger for Aβo. Field excitatory postsynaptic potentials indicate that fragments of NL-1 protect hippocampal neurons from the impairment induced by Aβo. To our knowledge, this is the first report of the interaction between this extracellular fragment of NL-1 and Aβo, strongly suggest that NL-1 facilitates the targeting of Aβo to the postsynaptic regions of excitatory synapses.

13 Article ADAM10 gene expression in the blood cells of Alzheimer's disease patients and mild cognitive impairment subjects. 2015

Manzine, Patricia Regina / Marcello, Elena / Borroni, Barbara / Kamphuis, Willem / Hol, Elly / Padovani, Alessandro / Nascimento, Carla Crispim / de Godoy Bueno, Patricia / Assis Carvalho Vale, Francisco / Iost Pavarini, Sofia Cristina / Di Luca, Monica / Cominetti, Márcia Regina. ·a Department of Gerontology , Federal University of São Carlos , São Carlos , SP , Brazil . ·Biomarkers · Pubmed #26220620.

ABSTRACT: ADAM10 is a potential biomarker for Alzheimer's disease (AD). ADAM10 protein levels are reduced in platelets of AD patients. The aim was to verify the total blood and platelet ADAM10 gene expression in AD patients and to compare with mild cognitive impairment (MCI) and healthy subjects. No significant differences in ADAM10 gene expression were observed. Therefore, the decrease of ADAM10 protein in platelets of AD patients is not caused by a reduction in ADAM10 mRNA. Further studies must be performed to investigate other pathways in the down regulation of ADAM10 protein.

14 Article SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation. 2014

Saraceno, C / Marcello, E / Di Marino, D / Borroni, B / Claeysen, S / Perroy, J / Padovani, A / Tramontano, A / Gardoni, F / Di Luca, M. ·Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy. · Department of Physics, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy. · Department of Neurological Sciences, University of Brescia, 25125 Brescia, Italy. · 1] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France [2] Inserm, U661, Montpellier, France [3] Universités de Montpellier 1 and 2, UMR-5203, Montpellier, France. · 1] Department of Physics, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy [2] Institute Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy. ·Cell Death Dis · Pubmed #25429624.

ABSTRACT: A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. Such mechanism is essential for ADAM10 trafficking from the Golgi outposts to the synapse, but does not affect ADAM10 transport from the endoplasmic reticulum. Notably, this process is altered in Alzheimer's disease brains. These results help in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and can constitute an innovative therapeutic strategy to finely tune ADAM10 shedding activity towards APP.

15 Article Modeling Alzheimer's disease: from past to future. 2013

Saraceno, Claudia / Musardo, Stefano / Marcello, Elena / Pelucchi, Silvia / Di Luca, Monica. ·Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano Milano, Italy ; Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano Milano, Italy. ·Front Pharmacol · Pubmed #23801962.

ABSTRACT: Alzheimer's disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations, as more people live long enough to become affected. Although AD is placing a considerable and increasing burden on society, it represents the largest unmet medical need in neurology, because current drugs improve symptoms, but do not have profound disease-modifying effects. Although AD pathogenesis is multifaceted and difficult to pinpoint, genetic and cell biological studies led to the amyloid hypothesis, which posits that amyloid β (Aβ) plays a pivotal role in AD pathogenesis. Amyloid precursor protein (APP), as well as β- and γ-secretases are the principal players involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. The association of early onset familial AD with mutations in the APP and γ-secretase components provided a potential tool of generating animal models of the disease. However, a model that recapitulates all the aspects of AD has not yet been produced. Here, we face the problem of modeling AD pathology describing several models, which have played a major role in defining critical disease-related mechanisms and in exploring novel potential therapeutic approaches. In particular, we will provide an extensive overview on the distinct features and pros and contras of different AD models, ranging from invertebrate to rodent models and finally dealing with computational models and induced pluripotent stem cells.

16 Article Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. 2013

Marcello, Elena / Saraceno, Claudia / Musardo, Stefano / Vara, Hugo / de la Fuente, Alerie Guzman / Pelucchi, Silvia / Di Marino, Daniele / Borroni, Barbara / Tramontano, Anna / Pérez-Otaño, Isabel / Padovani, Alessandro / Giustetto, Maurizio / Gardoni, Fabrizio / Di Luca, Monica. ·Università degli Studi di Milano, Dipartimento di Scienze Farmacologiche e Biomolecolari and Centre of Excellence on Neurodegenerative Diseases, Milan, Italy. ·J Clin Invest · Pubmed #23676497.

ABSTRACT: A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.

17 Article SAP97-mediated local trafficking is altered in Alzheimer disease patients' hippocampus. 2012

Marcello, Elena / Epis, Roberta / Saraceno, Claudia / Gardoni, Fabrizio / Borroni, Barbara / Cattabeni, Flaminio / Padovani, Alessandro / Di Luca, Monica. ·Università degli Studi di Milano, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, Milan, Italy. ·Neurobiol Aging · Pubmed #20980075.

ABSTRACT: Synapse-asssociated protein-97 (SAP97) is responsible for the trafficking of both glutamate receptor subunits, GluR1 and NR2A, and α-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 pathology.

18 Article Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease. 2010

Epis, Roberta / Marcello, Elena / Gardoni, Fabrizio / Vastagh, Csaba / Malinverno, Matteo / Balducci, Claudia / Colombo, Alessio / Borroni, Barbara / Vara, Hugo / Dell'Agli, Mario / Cattabeni, Flamino / Giustetto, Maurizio / Borsello, Tiziana / Forloni, Gianluigi / Padovani, Alessandro / Di Luca, Monica. ·Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, 20133 Milan, Italy. ·Brain · Pubmed #20805102.

ABSTRACT: We describe here an innovative, non-transgenic animal model of Alzheimer's disease. This model mimics early stages of sporadic disease, which represents the vast majority of cases. The model was obtained by interfering with the complex between a disintegrin and metalloproteinase domain containing protein 10 (ADAM10), the main α-secretase candidate, and its partner, synapse-associated protein 97, a protein of the postsynaptic density-membrane associated guanylate kinase family. Association of ADAM10 with synapse-associated protein 97 governs enzyme trafficking and activity at synapses. Interfering with the ADAM10/synapse-associated protein 97 complex for 2 weeks by means of a cell-permeable peptide strategy is sufficient to shift the metabolism of the amyloid precursor protein towards amyloidogenesis and allows the reproduction of initial phases of sporadic Alzheimer's disease. After 2 weeks of treatment, we detected progressive Alzheimer's disease-like neuropathology, with an increase of β-amyloid aggregate production and of tau hyperphosphorylation, and a selective alteration of N-methyl-d-aspartic acid receptor subunit composition in the postsynaptic compartment of mouse brain. Behavioural and electrophysiological deficits were also induced by peptide treatment.