title: Neutralization of TNFSF10 ameliorates functional outcome in a murine model of Alzheimer's disease.
abstract: Alzheimer's disease is one of the most common causes of death worldwide, with poor treatment options. A tissue landmark of Alzheimer's disease is accumulation of the anomalous protein amyloid-β in specific brain areas. Whether inflammation is an effect of amyloid-β on the Alzheimer's disease brain, or rather it represents a cause for formation of amyloid plaques and intracellular tangles remains a subject of debate. TNFSF10, a proapoptotic cytokine of the TNF superfamily, is a mediator of amyloid-β neurotoxicity. Here, we demonstrate that blocking TNFSF10 by administration of a neutralizing monoclonal antibody could attenuate the amyloid-β-induced neurotoxicity in a triple transgenic mouse model of Alzheimer's disease (3xTg-AD). The effects of TNFSF10 neutralization on either cognitive parameters, as well as on the expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP were studied in the hippocampus of 3xTg-AD mice. Treatment with the TNFSF10 neutralizing antibody resulted in dramatic improvement of cognitive parameters, as assessed by the Morris water maze test and the novel object recognition test. These results were correlated with decreased protein expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP in the hippocampus. Finally, neutralization of TNFSF10 results in functional improvement and restrained immune/inflammatory response in the brain of 3xTg-AD mice in vivo. Thus, it is plausible to regard the TNFSF10 system as a potential target for efficacious treatment of amyloid-related disorders.
authors.affiliation: 1 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, 95125 Catania, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cantarella
authors.affiliation: 1 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, 95125 Catania, Italy 2 Li-Sa Laboratory, Department of Experimental Medicine, Section of Medical Physiopathology, Endocrinology and Nutrition, University of Roma 'La Sapienza', 00161 Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Benedetto
authors.affiliation: 3 Department of Bio-Medical Sciences, Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Puzzo
authors.affiliation: 3 Department of Bio-Medical Sciences, Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Privitera
authors.affiliation: 4 Department of Bio-Medical Sciences, Section of Anatomy and Histology, University of Catania, 95125 Catania, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Loreto
authors.affiliation: 5 Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, 95125 Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Saccone
authors.affiliation: 4 Department of Bio-Medical Sciences, Section of Anatomy and Histology, University of Catania, 95125 Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Giunta
authors.affiliation: 3 Department of Bio-Medical Sciences, Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Palmeri
authors.affiliation: 1 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, 95125 Catania, Italy bernardi@unict.it.
authors.forename: Renato
authors.initials: R
authors.lastname: Bernardini
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016875:tau Proteins
keywords: TNFSF10; amyloid-β; hippocampus; inflammation; neurodegeneration