Inhibition of Pro-Inflammatory Microglia with Minocycline Improves Cognitive and Sleep-Wake Dysfunction Under Respiratory Stress in a Sporadic Model for Alzheimer's Disease

Author(s)

Vicente, Mariane C. ; Stabile, Angelita M. ; Amorim, Mateus ; Anibal Silva, Conceicao E. ; Patrone, Luis Gustavo A. ; Cunha, Thiago M. ; Bicego, Kenia C. ; Almeida, Maria C. ; Carrettiero, Daniel C. ; Gargaglioni, Luciane H.

• Document type: Journal article
• Source: JOURNAL OF ALZHEIMER'S DISEASE; v. 95, n. 1, p. 21-pg., 2023-01-01.

Abstract

Background: Neuroinflammation in Alzheimer's disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-beta peptide (A beta). 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 A beta, 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-alpha. 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. (AU)

• FAPESP's process: 16/04412-0 - Neuroanatomical and functional alterations of the respiratory system during sleep and wakefulness in an experimental model for Alzheimer's Disease
• Grantee: Mariane Cristine Vicente
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/24577-3 - Neuroanatomical and functional alterations of the respiratory system during sleep and wakefulness in an experimental model for Alzheimer's disease
• Grantee: Luciane Helena Gargaglioni Batalhão
• Support Opportunities: Regular Research Grants