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Role of Liver X Receptor in AD Pathophysiology.

Sandoval-Hernández AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G - PLoS ONE (2015)

Bottom Line: In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus.The effect of GW3965 on synaptic function was protein synthesis dependent.Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Muerte Celular, Instituto de Genética Universidad Nacional de Colombia, Bogotá, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

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LXR agonist restores memory and cognition in the 3xTg-AD mice.Spatial learning and memory were evaluated by means of the MWM after 12 weeks of treatment with the LXR agonist GW3965. (A) Learning task: treated 3xTg-AD mice took significantly less time to learn the location of the hidden platform. Statistical significant differences were found by using two-way ANOVA. *** p<0.001. (B-D) Retention tasks: (B) latency to step-through place of platform in seconds. Significant differences were found by using ANOVA followed by Tukey's multiple comparison test; (C) 4X analysis: time spent nearest the platform; (D) Representative samples of paths taken during the retention task illustrate the marked preference between treated and untreated WT and 3xTg-AD mice. (E) Reversal learning: treated 3xTg-AD mice took significantly less time to learn the new location of the hidden platform after two days of trials. All data were expressed as mean ± S.E.M. *** represents p < 0.001 compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD. Cohort sizes were: WT, n = 7; WT treated, n = 10; 3xTg-AD untreated, n = 8; treated 3xTG, (Randomized Females and Males) n = 12. Learning task: all data were expressed as mean ± S.E.M. *** represents p < 0.001, compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD.
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pone.0145467.g001: LXR agonist restores memory and cognition in the 3xTg-AD mice.Spatial learning and memory were evaluated by means of the MWM after 12 weeks of treatment with the LXR agonist GW3965. (A) Learning task: treated 3xTg-AD mice took significantly less time to learn the location of the hidden platform. Statistical significant differences were found by using two-way ANOVA. *** p<0.001. (B-D) Retention tasks: (B) latency to step-through place of platform in seconds. Significant differences were found by using ANOVA followed by Tukey's multiple comparison test; (C) 4X analysis: time spent nearest the platform; (D) Representative samples of paths taken during the retention task illustrate the marked preference between treated and untreated WT and 3xTg-AD mice. (E) Reversal learning: treated 3xTg-AD mice took significantly less time to learn the new location of the hidden platform after two days of trials. All data were expressed as mean ± S.E.M. *** represents p < 0.001 compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD. Cohort sizes were: WT, n = 7; WT treated, n = 10; 3xTg-AD untreated, n = 8; treated 3xTG, (Randomized Females and Males) n = 12. Learning task: all data were expressed as mean ± S.E.M. *** represents p < 0.001, compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD.

Mentions: We initially examined the effects in cognition by using the Morris Water Maze (WMW) task to determine if a long term LXR-activation contributes to improvement of spatial learning and memory in 3xTg-AD mice. In the learning task (Fig 1A), untreated WT mice performed significantly better than untreated 3xTg-AD mice on 5 days of trials (p<0.001). When 3xTg-AD mice were treated with GW3965, there was no significant difference with WT in these tasks. No significant differences were observed between untreated and treated WT. In retention task (Fig 1B), untreated WT had significantly less time of latency to step through the platform than untreated 3xTg-AD mice (p<0.001); GW3965-treated 3xTg-AD mice had no significant differences with WT. No statistically significant differences in latency were observed between untreated and treated WT The retention task analyzed in a 4X proximity design showed that treated 3xTg-AD mice—compared with untreated 3xTg-AD mice—spent more time swimming near the platform (p<0.001). In addition, no significant differences were found between treated and untreated WT (Fig 1C and 1D). Spatial reversal training was also assessed and the results were similar to those obtained for learning task. Untreated WT performed significantly better than untreated 3xTg-AD mice on 2 days of trials and untreated 3xtg-AD mice did not show any significant decrease in latency of escape over 2 days of trials. When 3xTg-AD mice were treated with GW3965, there was no significant difference with WT in this task. No differences were observed between untreated and treated WT mice in any of the measures (Fig 1E). These data indicate that GW3965 improves the hippocampal-dependent behavior tested by MWM in 3xTg-AD and does not significantly affect performance in WT mice.


Role of Liver X Receptor in AD Pathophysiology.

Sandoval-Hernández AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G - PLoS ONE (2015)

LXR agonist restores memory and cognition in the 3xTg-AD mice.Spatial learning and memory were evaluated by means of the MWM after 12 weeks of treatment with the LXR agonist GW3965. (A) Learning task: treated 3xTg-AD mice took significantly less time to learn the location of the hidden platform. Statistical significant differences were found by using two-way ANOVA. *** p<0.001. (B-D) Retention tasks: (B) latency to step-through place of platform in seconds. Significant differences were found by using ANOVA followed by Tukey's multiple comparison test; (C) 4X analysis: time spent nearest the platform; (D) Representative samples of paths taken during the retention task illustrate the marked preference between treated and untreated WT and 3xTg-AD mice. (E) Reversal learning: treated 3xTg-AD mice took significantly less time to learn the new location of the hidden platform after two days of trials. All data were expressed as mean ± S.E.M. *** represents p < 0.001 compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD. Cohort sizes were: WT, n = 7; WT treated, n = 10; 3xTg-AD untreated, n = 8; treated 3xTG, (Randomized Females and Males) n = 12. Learning task: all data were expressed as mean ± S.E.M. *** represents p < 0.001, compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4697813&req=5

pone.0145467.g001: LXR agonist restores memory and cognition in the 3xTg-AD mice.Spatial learning and memory were evaluated by means of the MWM after 12 weeks of treatment with the LXR agonist GW3965. (A) Learning task: treated 3xTg-AD mice took significantly less time to learn the location of the hidden platform. Statistical significant differences were found by using two-way ANOVA. *** p<0.001. (B-D) Retention tasks: (B) latency to step-through place of platform in seconds. Significant differences were found by using ANOVA followed by Tukey's multiple comparison test; (C) 4X analysis: time spent nearest the platform; (D) Representative samples of paths taken during the retention task illustrate the marked preference between treated and untreated WT and 3xTg-AD mice. (E) Reversal learning: treated 3xTg-AD mice took significantly less time to learn the new location of the hidden platform after two days of trials. All data were expressed as mean ± S.E.M. *** represents p < 0.001 compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD. Cohort sizes were: WT, n = 7; WT treated, n = 10; 3xTg-AD untreated, n = 8; treated 3xTG, (Randomized Females and Males) n = 12. Learning task: all data were expressed as mean ± S.E.M. *** represents p < 0.001, compared with WT; ### represents p < 0.001 compared with untreated 3xTg-AD.
Mentions: We initially examined the effects in cognition by using the Morris Water Maze (WMW) task to determine if a long term LXR-activation contributes to improvement of spatial learning and memory in 3xTg-AD mice. In the learning task (Fig 1A), untreated WT mice performed significantly better than untreated 3xTg-AD mice on 5 days of trials (p<0.001). When 3xTg-AD mice were treated with GW3965, there was no significant difference with WT in these tasks. No significant differences were observed between untreated and treated WT. In retention task (Fig 1B), untreated WT had significantly less time of latency to step through the platform than untreated 3xTg-AD mice (p<0.001); GW3965-treated 3xTg-AD mice had no significant differences with WT. No statistically significant differences in latency were observed between untreated and treated WT The retention task analyzed in a 4X proximity design showed that treated 3xTg-AD mice—compared with untreated 3xTg-AD mice—spent more time swimming near the platform (p<0.001). In addition, no significant differences were found between treated and untreated WT (Fig 1C and 1D). Spatial reversal training was also assessed and the results were similar to those obtained for learning task. Untreated WT performed significantly better than untreated 3xTg-AD mice on 2 days of trials and untreated 3xtg-AD mice did not show any significant decrease in latency of escape over 2 days of trials. When 3xTg-AD mice were treated with GW3965, there was no significant difference with WT in this task. No differences were observed between untreated and treated WT mice in any of the measures (Fig 1E). These data indicate that GW3965 improves the hippocampal-dependent behavior tested by MWM in 3xTg-AD and does not significantly affect performance in WT mice.

Bottom Line: In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus.The effect of GW3965 on synaptic function was protein synthesis dependent.Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Muerte Celular, Instituto de Genética Universidad Nacional de Colombia, Bogotá, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

Show MeSH
Related in: MedlinePlus