title: Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease.
abstract: The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology.
authors.affiliation: 1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Collin
authors.affiliation: 1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.affiliation: 2 Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Göpfert
authors.affiliation: 1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Oroszlan-Szovik
authors.affiliation: 1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.affiliation: 1 Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland fiona.grueninger@roche.com.
authors.forename: Fiona
authors.initials: F
authors.lastname: Grüninger
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D012521:Sarcosine / Q000031:analogs & derivatives / Q000737:chemistry; D016875:tau Proteins / Q000276:immunology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D000911:Antibodies, Monoclonal; D016875:tau Proteins; C025231:sarkosyl; D012521:Sarcosine
keywords: lipid rafts; tau immunotherapy; tau/pS422 antibody