Thymidine and 2'-deoxyuridine reduce microglial activation and improve oxidative stress damage by modulating glycolytic metabolism on the Aβ 25-35 -induced brain injury.

Alzheimer's disease (AD) is a progressive disease with a long duration and complicated pathogenesis. Thymidine (Thy) and 2'-deoxyuridine (2'-De) are pyrimidines nucleotides that are associated with nervous system diseases. However, it remains unclear whether Thy and 2'-De exert neuroprotective effects in AD. Therefore, this study was conducted to explore the interventional effects and mechanisms of Thy and 2'-De on the Aβ _25-35 -induced brain injury. Donepezil (Do, 10 mg/kg/d), Thy (20 mg/kg/d), and 2'-De (20 mg/kg/d) were administered for 4 weeks after the injection of Aβ _25-35 peptides (200 μM, i.c.v.) to mice. UPLC-MS/MS method was performed to quantify Thy and 2'-De in the hippocampus of mice brain. The cognition ability, neuronal and mitochondria damage, and levels of Aβ _1-42 /Aβ _1-40 , p-Tau, Na ⁺ K ⁺ -ATPase, apoptosis, oxidative stress, immune cells, and Iba 1 ⁺ were measured in Aβ _25-35 -induced mice. The oxygen consumption (OCR) and extracellular acidification rate (ECAR) were measured using a seahorse analyzer in Aβ _25-35 -induced N9 cells. Moreover, 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was added to explore the mechanisms underlying the effects of Thy and 2'-De on Aβ _25-35 -induced N9 cells. The expression of Iba 1 ⁺ and levels of CD11b ⁺ and reactive oxygen species (ROS) were measured after treatment with Thy (5 μM) and 2'-De (10 μM) against 2-DG (5 mM) in Aβ _25-35 -induced N9 cells. The results suggested that Do, Thy, and 2'-De improved the cognition ability, attenuated the damage to hippocampus and mitochondria, downregulated the levels of Aβ _1-42 /Aβ _1-40 , p-Tau, Na ⁺ K ⁺ -ATPase, apoptosis, oxidative stress, and Iba 1 ⁺ , and regulated the immune response induced by Aβ _25-35 against the brain injury. Furthermore, Do, Thy, and 2'-De increased ATP production and inhibited glycolysis in Aβ _25-35 -induced N9 cells. Moreover, 2-DG enhanced the effects of drugs, reduced microglial activation, and attenuated oxidative stress to interfere with Aβ _25-35 -induced N9 cells. In conclusion, Thy and 2'-De reduced microglial activation and improved oxidative stress damage by modulating glycolytic metabolism on the Aβ _25-35 -induced brain injury.
Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.
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