Limits...
Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice.

Lull ME, Levesque S, Surace MJ, Block ML - PLoS ONE (2011)

Bottom Line: Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)(SL) mice.To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival.Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia, United States of America.

ABSTRACT

Background: NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)(SL)).

Methods: Four month old hAPP(751)(SL) mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months.

Results: Only hAPP(751)(SL) mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)(SL) mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)(SL) mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival.

Conclusions: Together, this study suggests that while hAPP(751)(SL) mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.

Show MeSH

Related in: MedlinePlus

Apocynin reduces the number of microglia in the cortex of hAPP(751)SL mice.Mice were treated daily with 15 mg/kg dextromethorphan (DM), 7.5 mg/kg DM, or 10 mg/kg apocynin for four months. The number of microglia was then counted for each group by staining with anti-CD11b antibody and each treatment group was compared to control. CD11b-stained microglia were only counted if they corresponded to a DAPI stained nuclei (data not shown). Representative images from each group of the stained microglia are shown in panel (A). Apocynin reduced the number of microglia in the cortex of hAPP(751)SL mice, whereas neither dose of DM reduced microglia number (B). *p<0.05 vs vehicle, 1-way ANOVA with Bonferroni post-hoc test.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105011&req=5

pone-0020153-g002: Apocynin reduces the number of microglia in the cortex of hAPP(751)SL mice.Mice were treated daily with 15 mg/kg dextromethorphan (DM), 7.5 mg/kg DM, or 10 mg/kg apocynin for four months. The number of microglia was then counted for each group by staining with anti-CD11b antibody and each treatment group was compared to control. CD11b-stained microglia were only counted if they corresponded to a DAPI stained nuclei (data not shown). Representative images from each group of the stained microglia are shown in panel (A). Apocynin reduced the number of microglia in the cortex of hAPP(751)SL mice, whereas neither dose of DM reduced microglia number (B). *p<0.05 vs vehicle, 1-way ANOVA with Bonferroni post-hoc test.

Mentions: The number of microglia in both the cortex and hippocampus of hAPP(751)SL mice with DM or apocynin treatment was counted using CD11b immunoreactivity. Decreases in the number of microglia in the cortex was observed in mice treated with 10 mg/kg apocynin (p<0.05; Figure 2). No changes were seen in the hippocampus (Table S1).


Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice.

Lull ME, Levesque S, Surace MJ, Block ML - PLoS ONE (2011)

Apocynin reduces the number of microglia in the cortex of hAPP(751)SL mice.Mice were treated daily with 15 mg/kg dextromethorphan (DM), 7.5 mg/kg DM, or 10 mg/kg apocynin for four months. The number of microglia was then counted for each group by staining with anti-CD11b antibody and each treatment group was compared to control. CD11b-stained microglia were only counted if they corresponded to a DAPI stained nuclei (data not shown). Representative images from each group of the stained microglia are shown in panel (A). Apocynin reduced the number of microglia in the cortex of hAPP(751)SL mice, whereas neither dose of DM reduced microglia number (B). *p<0.05 vs vehicle, 1-way ANOVA with Bonferroni post-hoc test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105011&req=5

pone-0020153-g002: Apocynin reduces the number of microglia in the cortex of hAPP(751)SL mice.Mice were treated daily with 15 mg/kg dextromethorphan (DM), 7.5 mg/kg DM, or 10 mg/kg apocynin for four months. The number of microglia was then counted for each group by staining with anti-CD11b antibody and each treatment group was compared to control. CD11b-stained microglia were only counted if they corresponded to a DAPI stained nuclei (data not shown). Representative images from each group of the stained microglia are shown in panel (A). Apocynin reduced the number of microglia in the cortex of hAPP(751)SL mice, whereas neither dose of DM reduced microglia number (B). *p<0.05 vs vehicle, 1-way ANOVA with Bonferroni post-hoc test.
Mentions: The number of microglia in both the cortex and hippocampus of hAPP(751)SL mice with DM or apocynin treatment was counted using CD11b immunoreactivity. Decreases in the number of microglia in the cortex was observed in mice treated with 10 mg/kg apocynin (p<0.05; Figure 2). No changes were seen in the hippocampus (Table S1).

Bottom Line: Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)(SL) mice.To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival.Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia, United States of America.

ABSTRACT

Background: NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)(SL)).

Methods: Four month old hAPP(751)(SL) mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months.

Results: Only hAPP(751)(SL) mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)(SL) mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)(SL) mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival.

Conclusions: Together, this study suggests that while hAPP(751)(SL) mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.

Show MeSH
Related in: MedlinePlus