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Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease.
Mol Psychiatry. 2010 Mar; 15(3):272-85, 228.MP

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-beta-peptide (Abeta) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Abeta neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist, has been shown to attenuate Abeta-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo, the effect of lithium and rosiglitazone on Abeta neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Abeta aggregates and Abeta oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in beta-catenin and by the inhibition of the glycogen synthase kinase-3beta. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.

Authors+Show Affiliations

Centro de Envejecimiento y Regeneración, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chille.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19621015

Citation

Toledo, E M., and N C. Inestrosa. "Activation of Wnt Signaling By Lithium and Rosiglitazone Reduced Spatial Memory Impairment and Neurodegeneration in Brains of an APPswe/PSEN1DeltaE9 Mouse Model of Alzheimer's Disease." Molecular Psychiatry, vol. 15, no. 3, 2010, pp. 272-85, 228.
Toledo EM, Inestrosa NC. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry. 2010;15(3):272-85, 228.
Toledo, E. M., & Inestrosa, N. C. (2010). Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Molecular Psychiatry, 15(3), 272-85, 228. https://doi.org/10.1038/mp.2009.72
Toledo EM, Inestrosa NC. Activation of Wnt Signaling By Lithium and Rosiglitazone Reduced Spatial Memory Impairment and Neurodegeneration in Brains of an APPswe/PSEN1DeltaE9 Mouse Model of Alzheimer's Disease. Mol Psychiatry. 2010;15(3):272-85, 228. PubMed PMID: 19621015.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. AU - Toledo,E M, AU - Inestrosa,N C, Y1 - 2009/07/21/ PY - 2009/7/22/entrez PY - 2009/7/22/pubmed PY - 2010/5/12/medline SP - 272-85, 228 JF - Molecular psychiatry JO - Mol Psychiatry VL - 15 IS - 3 N2 - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-beta-peptide (Abeta) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Abeta neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist, has been shown to attenuate Abeta-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo, the effect of lithium and rosiglitazone on Abeta neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Abeta aggregates and Abeta oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in beta-catenin and by the inhibition of the glycogen synthase kinase-3beta. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/19621015/Activation_of_Wnt_signaling_by_lithium_and_rosiglitazone_reduced_spatial_memory_impairment_and_neurodegeneration_in_brains_of_an_APPswe/PSEN1DeltaE9_mouse_model_of_Alzheimer's_disease_ L2 - https://doi.org/10.1038/mp.2009.72 DB - PRIME DP - Unbound Medicine ER -