TLR4 Inhibition Attenuate Facilitatory Effects of JQ1 on Learning & Memory Via Polarization of Microglia, and BDNF Expression in Alzheimer's Disease Model.

OBJECTIVE Neuroinflammation is a core event in the pathogenesis of Alzheimer's disease (AD), which is mediated by microglia. The present study aimed to investigate the effect of co-inhibition of Toll-like receptor (TLR4) and chromatin reader of BRD4 on cognition deficit, polarization of microglia, and Brain-derived neurotrophic factor in the hippocampus. METHODS Forty male Wistar rats were randomly divided into five groups: saline +saline, Aβ+saline, Aβ+JQ1(BRD4 inhibitor), Aβ+TAK242 (TLR4 inhibitor), Aβ+JQ1+TAK-2452, and received the related treatments. Then cognitive functions were assessed by passive avoidance learning (PAL) and Morris water maze (MWM) tests. Then, the polarization of microglia and BDNF level in the hippocampus, were measured using flow cytometry and western blotting, respectively. RESULTS Chronic intracerebroventricular administration of JQ1, either alone or in combination with TAK-242, significantly reduced escape latency and increased the time spent in the target quadrant (TTS) during the probe test of the Morris Water Maze (MWM), compared with the Aβ + saline group (p < 0.05). In contrast, TAK-242 alone prolonged escape latency and reduced TTS (p < 0.05). Moreover, JQ1 treatment markedly elevated the M2/M1 microglial polarization and the mBDNF/proBDNF ratio in the hippocampus (p < 0.05), suggesting that JQ1 promotes neuroprotective and cognitive function mechanisms in this model. CONCLUSION Our results indicate that JQ1 successfully improves learning and memory in the rat model of Alzheimer's disease, primarily by inducing the transcription of BDNF expression and suppressing inflammatory factors related to the M1 microglia. In contrast, co-treatment with a TLR4 inhibitor attenuate both spatial and aversive memories, probably through a decrease in BDNF expression.

• Publication year

  2025

• Venue

  Behavioural Brain Research

• Publication date

  2025-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.bbr.2025.115919PMID 41218737
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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