Inhibition of Pro-Inflammatory Microglia with Minocycline Improves Cognitive and Sleep-Wake Dysfunction Under
Mariane C Vicente1,2, Julia L Paneghini1, Angelita M Stabile3
1Department of Animal Morphology and Physiology, Sao Paulo State University - UNESP/FCAV, Jaboticabal, SP, Brazil.
Background:
Neuroinflammation in Alzheimer's disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-β peptide (Aβ). Previously, we demonstrated an increased expression of this peptide in the locus coeruleus (LC) in a sporadic model for AD (streptozotocin, STZ; 2 mg/kg, ICV). We hypothesized that the STZ-AD model exhibits neuroinflammation, and treatment with an inhibitor of microglia (minocycline) can reverse the cognitive, respiratory, sleep, and molecular disorders of this model.
Objective:
To evaluate the effect of minocycline treatment in STZ model disorders.
Methods:
We treated control and STZ-treated rats for five days with minocycline (30 mg/kg, IP) and evaluated cognitive performance, chemoreflex response to hypercapnia and hypoxia, and total sleep time. Additionally, quantification of Aβ, microglia analyses, and relative expression of cytokines in the LC were performed.
Results:
Minocycline treatment improved learning and memory, which was concomitant with a decrease in microglial cell density and re-establishment of morphological changes induced by STZ in the LC region. Minocycline did not reverse the STZ-induced increase in CO2 sensitivity during wakefulness. However, it restored the daytime sleep-wake cycle in STZ-treated animals to the same levels as those observed in control animals. In the LC, levels of A and expression of Il10, Il1b, and Mcp1 mRNA remained unaffected by minocycline, but we found a strong trend of minocycline effect on Tnf- α.
Conclusion:
Our findings suggest that minocycline effectively reduces microglial recruitment and the inflammatory morphological profile in the LC, while it recovers cognitive performance and restores the sleep-wake pattern impaired by STZ.
Insights
Minocycline treatment improved cognitive and sleep deficits in a rat model of Alzheimer's disease (AD) by reducing neuroinflammation in the locus coeruleus (LC). This study highlights minocycline's potential for AD therapy.
Area of Science:
- Neuroscience
- Pharmacology
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) involves neuroinflammation driven by activated microglia and amyloid-beta (Aβ) peptide accumulation.
- A previous study showed increased Aβ in the locus coeruleus (LC) of a sporadic AD rat model (STZ).
- This model was hypothesized to exhibit neuroinflammation, cognitive, respiratory, sleep, and molecular disorders.
Purpose of the Study:
- To evaluate the therapeutic effects of minocycline, a microglia inhibitor, on STZ-induced disorders in a rat model.
- To assess minocycline's impact on cognitive function, respiratory control, sleep patterns, and molecular markers in the LC.
Main Methods:
- Rats were treated with streptozotocin (STZ) to model sporadic AD and subsequently with minocycline.
- Evaluated cognitive performance, chemoreflex response, and total sleep time.
- Quantified Aβ, analyzed microglia, and measured cytokine mRNA expression in the LC.
Main Results:
- Minocycline improved learning and memory in STZ-treated rats.
- Reduced microglial density and restored morphology in the LC.
- Restored the daytime sleep-wake cycle but did not reverse increased CO2 sensitivity.
- Aβ and some cytokine levels remained unchanged, with a trend for TNF-α.
Conclusions:
- Minocycline effectively reduces microglial activation and neuroinflammation in the LC of the STZ-AD model.
- Minocycline treatment recovers cognitive performance and normalizes the sleep-wake cycle.
- Suggests minocycline as a potential therapeutic agent for cognitive and sleep disturbances in AD.
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