Compound AD16 Reduces Amyloid Plaque Deposition and Modifies Microglia in a Transgenic Mouse Model of Alzheimer's Disease
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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Ping Sun1,2, Hu Yue1, Qi Xing2
1Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
Abstract:
Microglial dysfunction is involved in the pathological cascade of Alzheimer's disease (AD). The regulation of microglial function may be a novel strategy for AD therapy. We previously reported the discovery of AD16, an antineuroinflammatory molecule that could improve learning and memory in the AD model. Here, we studied its properties of microglial modification in the AD mice model. In this study, AD16 reduced interleukin-1β (IL-1β) expression in the lipopolysaccharide-induced IL-1β-Luc transgenic mice model. Compared with mice receiving placebo, the group treated with AD16 manifested a significant reduction of microglial activation, plaque deposition, and peri-plaques microgliosis, but without alteration of the number of microglia surrounding the plaque. We also found that AD16 decreased senescent microglial cells marked with SA-β-gal staining. Furthermore, altered lysosomal positioning, enhanced Lysosomal Associated Membrane Protein 1 (LAMP1) expression, and elevated adenosine triphosphate (ATP) concentration were found with AD16 treatment in lipopolysaccharide-stimulated BV2 microglial cells. The underlying mechanisms of AD16 might include regulating the microglial activation/senescence and recovery of its physiological function via the improvement of lysosomal function. Our findings provide new insights into the AD therapeutic approach through the regulation of microglial function and a promising lead compound for further study.
Insights
AD16, an antineuroinflammatory molecule, reduces microglial activation and plaque deposition in Alzheimer's disease (AD) models. It also decreases senescent microglia and improves lysosomal function, offering a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial dysfunction is a key factor in Alzheimer's disease (AD) pathogenesis.
- Targeting microglial function presents a novel therapeutic avenue for AD.
- Previous research identified AD16 as an antineuroinflammatory molecule improving cognitive function in AD models.
Purpose of the Study:
- To investigate the microglial modification properties of AD16 in an Alzheimer's disease mouse model.
- To elucidate the underlying mechanisms by which AD16 exerts its effects on microglia.
Main Methods:
- Utilized a lipopolysaccharide-induced IL-1β-Luc transgenic mice model to assess AD16's effect on interleukin-1β (IL-1β) expression.
- Quantified microglial activation, plaque deposition, and peri-plaques microgliosis in AD mice treated with AD16 versus placebo.
- Assessed senescent microglial cells using SA-β-gal staining.
- Examined lysosomal function, including positioning, Lysosomal Associated Membrane Protein 1 (LAMP1) expression, and adenosine triphosphate (ATP) concentration in lipopolysaccharide-stimulated BV2 microglial cells.
Main Results:
- AD16 significantly reduced IL-1β expression.
- AD16 treatment led to decreased microglial activation, plaque deposition, and peri-plaques microgliosis without altering microglial numbers around plaques.
- AD16 decreased the number of senescent microglial cells.
- In vitro studies showed AD16 treatment improved lysosomal positioning, increased LAMP1 expression, and elevated ATP concentration in microglial cells.
Conclusions:
- AD16 demonstrates potent anti-neuroinflammatory effects by modulating microglial activation and senescence.
- The therapeutic benefits of AD16 may stem from its ability to restore physiological microglial function through enhanced lysosomal activity.
- AD16 represents a promising lead compound for developing new Alzheimer's disease therapies targeting microglial pathways.
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