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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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Related in: MedlinePlus

Tau pathology is not significantly reduced by LXR activation.(A-B) Presence of aggregated phospho-tau in brains of treated and untreated mice groups was evaluated by immunohistochemistry with anti-phospho-tau antibody (AT-8). (C-D) No significant changes were found in the quantification of aggregated phospho-tau occupied area within the hippocampus or cortex in treated mice. Data were expressed as mean ± S.E.M. Statistical analysis was done by one way ANOVA followed by Tukey's multiple comparison test. n = 4 Females per 3xTg-AD group.
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pone.0145467.g003: Tau pathology is not significantly reduced by LXR activation.(A-B) Presence of aggregated phospho-tau in brains of treated and untreated mice groups was evaluated by immunohistochemistry with anti-phospho-tau antibody (AT-8). (C-D) No significant changes were found in the quantification of aggregated phospho-tau occupied area within the hippocampus or cortex in treated mice. Data were expressed as mean ± S.E.M. Statistical analysis was done by one way ANOVA followed by Tukey's multiple comparison test. n = 4 Females per 3xTg-AD group.

Mentions: To assess whether LXR-activation induced changes in amyloid plaque load and phosphorylated-Tau and if these changes were associated with the cognitive improvement observed, we performed immunohistochemistry analysis by using DAB detection and Thio-S staining. No significant differences in the amyloid plaque load or soluble Aβ (RIPA soluble Aβ (1–40) and RIPA soluble Aβ (1–42) were observed (Fig 2); neither changes were observed in aggregated phospho-tau (Fig 3A and 3B). Thio-S staining analysis to evaluate protein aggregation, showed no significant difference between treated and untreated animals (Figure A and Figure B in S1 File).


Role of Liver X Receptor in AD Pathophysiology.

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

Tau pathology is not significantly reduced by LXR activation.(A-B) Presence of aggregated phospho-tau in brains of treated and untreated mice groups was evaluated by immunohistochemistry with anti-phospho-tau antibody (AT-8). (C-D) No significant changes were found in the quantification of aggregated phospho-tau occupied area within the hippocampus or cortex in treated mice. Data were expressed as mean ± S.E.M. Statistical analysis was done by one way ANOVA followed by Tukey's multiple comparison test. n = 4 Females per 3xTg-AD group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145467.g003: Tau pathology is not significantly reduced by LXR activation.(A-B) Presence of aggregated phospho-tau in brains of treated and untreated mice groups was evaluated by immunohistochemistry with anti-phospho-tau antibody (AT-8). (C-D) No significant changes were found in the quantification of aggregated phospho-tau occupied area within the hippocampus or cortex in treated mice. Data were expressed as mean ± S.E.M. Statistical analysis was done by one way ANOVA followed by Tukey's multiple comparison test. n = 4 Females per 3xTg-AD group.
Mentions: To assess whether LXR-activation induced changes in amyloid plaque load and phosphorylated-Tau and if these changes were associated with the cognitive improvement observed, we performed immunohistochemistry analysis by using DAB detection and Thio-S staining. No significant differences in the amyloid plaque load or soluble Aβ (RIPA soluble Aβ (1–40) and RIPA soluble Aβ (1–42) were observed (Fig 2); neither changes were observed in aggregated phospho-tau (Fig 3A and 3B). Thio-S staining analysis to evaluate protein aggregation, showed no significant difference between treated and untreated animals (Figure A and Figure B in S1 File).

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