title: Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation.
abstract: The recent studies of others and of us showing robust efficacy of anti-tangle immunotherapy, directed against phosphorylated (phos)-tau protein, may pave the way to clinical trials of phos-tau immunotherapy in Alzheimer's-disease and other tauopathies. At this stage addressing the safety of the phos-tau-immunotherapy is highly needed, particularly since we have previously shown the neurotoxic potential of tau-immunotherapy, specifically of full-length unphosphorylated-tau vaccine under a CNS-proinflammatory milieu [induced by emulsification in complete-Freund's-adjuvant (CFA) and pertussis-toxin (PT)] in young wild-type (WT)-mice. The aim of our current study was to address safety aspects of the phos-tau-immunotherapy in both neurofibrillary-tangle (NFT)-mice as well as in WT-mice, under challenging conditions of repeated immunizations with phos-tau peptides under a CNS-proinflammatory milieu. NFT- and WT-mice were repeatedly immunized (7 injections in adult-, 4 in aged-mice) with phos-tau peptides emulsified in CFA-PT. A paralytic disease was evident in the phos-tau-immunized adult NFT-mice, developing progressively to 26.7% with the number of injections. Interestingly, the WT-mice were even more prone to develop neuroinflammation following phos-tau immunization, affecting 75% of the immunized mice. Aged mice were less prone to neuroinflammatory manifestations. Anti-phos-tau antibodies, detected in the serum of immunized mice, partially correlated with the neuroinflammation in WT-mice. This points that repeated phos-tau immunizations in the frame of a proinflammatory milieu may be encephalitogenic to tangle-mice, and more robustly to WT-mice, indicating that - under certain conditions - the safety of phos-tau immunotherapy is questionable.
authors.affiliation: The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lea
authors.initials: L
authors.lastname: Rozenstein-Tsalkovich
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Lourbopoulos
authors.forename: Evangelia
authors.initials: E
authors.lastname: Nousiopoulou
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Kassis
authors.forename: Oded
authors.initials: O
authors.lastname: Abramsky
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Karussis
authors.forename: Hanna
authors.initials: H
authors.lastname: Rosenmann
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D007114:Immunization / Q000009:adverse effects*; D007167:Immunotherapy / Q000009:adverse effects*; D016874:Neurofibrillary Tangles / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D024801:Tauopathies / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D016875:tau Proteins / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism
chemical_list: D016875:tau Proteins
keywords: Alzheimer's-disease; Immunotherapy; Neurofibrillary-tangles; Phosphorylated-tau; Tau protein; Tauopathy