Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice
Melinda E Lull1, Shannon Levesque, Michael J Surace
1Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia, United States of America.
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.
Insights
Apocynin reduced plaque size and microglia in Alzheimer
Area of Science:
- Neuroscience and Pharmacology
- Alzheimer's Disease Research
Background:
- NADPH oxidase contributes to neuroinflammation and Alzheimer's Disease (AD) progression.
- Microglial activation is a key factor in AD pathogenesis.
Purpose of the Study:
- To evaluate the efficacy of NADPH oxidase inhibitors apocynin and dextromethorphan (DM) in mitigating learning deficits and neuropathology.
- To assess the impact of these inhibitors on amyloid precursor protein transgenic mice (hAPP(751)(SL)).
Main Methods:
- Four-month-old hAPP(751)(SL) mice were administered daily doses of saline, DM (15 mg/kg or 7.5 mg/kg), or apocynin (10 mg/kg) via gavage for four months.
- Evaluated learning and memory tasks, synaptic density, plaque load, microglial numbers, and markers of neuroinflammation and oxidative stress.
Main Results:
- Apocynin treatment significantly reduced plaque size and cortical microglial numbers in hAPP(751)(SL) mice.
- Neither apocynin nor DM significantly improved learning and memory or synaptic density.
- Low levels of neuroinflammation and oxidative stress were observed in the mice, unaffected by drug treatments.
Conclusions:
- The hAPP(751)(SL) mouse model may not fully represent AD-associated neuroinflammation at 8 months of age.
- Apocynin demonstrated therapeutic potential by reducing plaque size and microglial numbers, potentially through mechanisms independent of anti-inflammatory effects.
