Tags

Type your tag names separated by a space and hit enter

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.
J Neurochem. 2006 Dec; 99(6):1445-55.JN

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.

Links

Aggregator Full Text

Authors+Show Affiliations

Engel T
Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid, Madrid, Spain.
Goñi-Oliver P
No affiliation info available
Lucas JJ
No affiliation info available
Avila J
No affiliation info available
Hernández F
No affiliation info available

MeSH

Age FactorsAnimalsAtrophyBlotting, WesternDoxycyclineDrug Administration ScheduleGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHippocampusHumansImmunohistochemistryLithiumMiceMice, TransgenicMicroscopy, ImmunoelectronMicrotubule-Associated ProteinsNeurofibrillary TanglesNeuronsNuclear ProteinsOrganic ChemicalsPhosphorylationt-Complex Genome Regiontau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17059563

Citation

Engel, Tobias, et al. "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." Journal of Neurochemistry, vol. 99, no. 6, 2006, pp. 1445-55.
Engel T, Goñi-Oliver P, Lucas JJ, et al. 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. J Neurochem. 2006;99(6):1445-55.
Engel, T., Goñi-Oliver, P., Lucas, J. J., Avila, J., & Hernández, F. (2006). 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. Journal of Neurochemistry, 99(6), 1445-55.
Engel T, et al. 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. J Neurochem. 2006;99(6):1445-55. PubMed PMID: 17059563.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Engel,Tobias, AU - Goñi-Oliver,Paloma, AU - Lucas,José J, AU - Avila,Jesús, AU - Hernández,Félix, Y1 - 2006/10/24/ PY - 2006/10/25/pubmed PY - 2007/2/16/medline PY - 2006/10/25/entrez SP - 1445 EP - 55 JF - Journal of neurochemistry JO - J Neurochem VL - 99 IS - 6 N2 - 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. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17059563/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_ L2 - https://doi.org/10.1111/j.1471-4159.2006.04139.x DB - PRIME DP - Unbound Medicine ER -