title: Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach.
abstract: Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.
authors.affiliation: Alzheimer&Tauopathies, Centre de Recherches Jean-Pierre Aubert, Lille, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Troquier
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Caillierez
authors.forename: Sylvie
authors.initials: S
authors.lastname: Burnouf
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Fernandez-Gomez
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Grosjean
authors.forename: Nadege
authors.initials: N
authors.lastname: Zommer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Susanna
authors.initials: S
authors.lastname: Schraen-Maschke
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.forename: Luc
authors.initials: L
authors.lastname: Buee
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000097:blood; D003072:Cognition Disorders / Q000209:etiology / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D010455:Peptides; D016875:tau Proteins; D012694:Serine