title: Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert.
abstract: Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3beta in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3beta; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3beta overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates.
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Paloma
authors.initials: P
authors.lastname: Goñi-Oliver
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
mesh_terms: D000367:Age Factors; D000818:Animals; D001284:Atrophy / Q000473:pathology / Q000517:prevention & control; D015153:Blotting, Western / Q000379:methods; D004318:Doxycycline / Q000008:administration & dosage; D004334:Drug Administration Schedule; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008094:Lithium / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D009930:Organic Chemicals; D010766:Phosphorylation / Q000187:drug effects; D056427:t-Complex Genome Region; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D009930:Organic Chemicals; D016875:tau Proteins; C419142:thiazin red; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004318:Doxycycline