Abstract
Communication between astrocytes and neurons has a profound effect on the pathophysiology of Alzheimer’s disease (AD). Astrocytes regulate homeostasis and increase synaptic plasticity in physiological situations, however, they become activated during the progression of AD. Whether or not these reactions are supportive or detrimental for the central nervous system have not been understood yet. Considering epigenetic regulation of neuroinflammatory genes by chromatin readers, particularly bromodomain and extraterminal domain (BET) family, here we examined the effect of chronic co-inhibition of astrocytes metabolism (with fluorocitrate) and also BRD4 (with JQ1) on cognition deficit at early stages of AD. Forty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intrahippocampal injection of Aβ1-42 (4 μg/8 μl/rat). Then animals were divided into five groups of Saline+DMSO, Aβ + saline+DMSO, Aβ + JQ1, Aβ + FC (fluorocitrate), and Aβ + JQ1 + FC and received the related treatments. Two weeks later, spatial memory was recorded by Morris Water Maze (MWM), and the levels of phosphorylated cyclic-AMP response element binding protein (CREB), postsynaptic density 95 (PSD95), synaptophysin (SYP), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus by western blotting and RT-qPCR. Administration of JQ1 significantly improved both acquisition and retrieval of spatial memory, which were evident by decreased escape latency and increased total time spent (TTS) in target quadrant, and significant rise in p-CREB, PSD95, and synaptophysin compared with Aβ + saline+DMSO group. In contrast, both groups receiving FC demonstrated memory decline, and reduction in p-CREB, PSD95 and synaptophysin in parallel with increase in TNF-α. Our data indicate that chronic inhibition of BRD4 significantly restores memory impaired by amyloid β partly via CREB signaling and upregulating synaptic proteins of PSD95 and synaptophysin. However, inhibition of astrocytes nullifies the memory-boosting effects of JQ1 and reduces CREB/PSD95/synaptophysin levels in hippocampus.
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The datasets generated during and/or analyzed during the current study are available within the supplementary materials.
Abbreviations
- Aβ:
-
Amyloid beta
- AD:
-
Alzheimer’s disease
- BRD4:
-
Bromodomain-containing protein 4
- Ca2+ :
-
Calcium ion
- CREB:
-
cAMP-response element binding protein
- FC:
-
Fluorocitrate
- MWM:
-
Morris water maze
- NF-κB:
-
Nuclear factor kappa B
- NMDAR :
-
N-methyl D-aspartate receptor
- p-CREB :
-
Phosphorylated cAMP-response element binding protein
- PSD95 :
-
Postsynaptic density 95
- P-TEFb :
-
Positive transcription elongation factor
- RT-qPCR:
-
Real-time quantitative polymerase chain reaction
- SYP:
-
Synaptophysin
- TNF-α:
-
Tumor necrosis factor alpha
- TTS:
-
Total time spent in target quadrant
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The authors thank Dr. Nozhat Zebardast for her technical support and Hamid Morrovati for his cooperation in animal handling during surgery.
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This study was supported by Grants from Research Council of Guilan University of Medical Sciences (Grant No. GUMS 98032706).
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PB designed and supervised the experiment, prepared first draft and revised manuscript. AE performed and analyzed the real-time and western blotting, also actively cooperated in manuscript revising. RN and MB performed the behavioral experiments and analyzed data. All authors read and approved the final manuscript.
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Nikkar, R., Esmaeili-bandboni, A., Badrikoohi, M. et al. Effects of inhibiting astrocytes and BET/BRD4 chromatin reader on spatial memory and synaptic proteins in rats with Alzheimer’s disease. Metab Brain Dis 37, 1119–1131 (2022). https://doi.org/10.1007/s11011-022-00940-7
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DOI: https://doi.org/10.1007/s11011-022-00940-7