Effects of inhibiting astrocytes and BET/BRD4 chromatin reader on spatial memory and synaptic proteins in rats with Alzheimer's disease.

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 Aß1-42 (4 µg/8 µl/rat). Then animals were divided into five groups of Saline+DMSO, Aß + saline+DMSO, Aß + JQ1, Aß + FC (fluorocitrate), and Aß + 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 Aß + 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 ß 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.

Simultaneous administration of bromodomain and histone deacetylase I inhibitors alleviates cognition deficit in Alzheimer's model of rats.

BACKGROUND: Histone deacetylases (HDACs) target various genes responsible for cognitive functions. However, chromatin readers, particularly bromodomain-containing protein 4 (BRD4), are capable to change the final products of genes. The objective of this study was to evaluate the simultaneous effects of inhibition of HDACs and BRD4 on spatial and aversive memories impaired by amyloid ß (Aß) in a rat model of Alzheimer's disease (AD) considering CREB and TNF-α signaling. METHODS: Forty male Wistar rats aged 3 months were randomly divided into five groups: saline +DMSO, Aß+saline+DMSO, Aß+JQ1, Aß+MS-275, Aß+JQ1+MS-275, and received the related treatments. MS-275, is the second generation of HDACs inhibitor, and JQ1 is a potent inhibitor of the BET family of bromodomain proteins in mammals. After the treatments, cognitive function was assessed by Morris water maze (MWM) and passive avoidance learning (PAL). The hippocampal level of mRNA for CREB and TNF-α, and also phosphorylated CREB were measured using real-time PCR and western blotting respectively. RESULTS: Administration of JQ1 and MS-275, either separately or simultaneously, improved acquisition and retrieval of spatial and aversive memories as it was evident by decreased escape latency and increased time spent in the target quadrant (TTS) in Morris water maze (MWM), together with increase in step-through latency, but reduced time spent in the dark zone time in passive avoidance learning (PAL) compared with Aß+saline+DMSO. Furthermore, there was a significant rise in the hippocampal level of CREB mRNA and phosphorylated CREB, but a reduction in TNF-α expression in comparison with Aß + Saline. CONCLUSION: Simultaneous administration of JQ1 and MS-275 improves acquisition and retrieval of both spatial and aversive memories partly via CREB and TNF-α signaling with no superiority to monotherapy.

Synergistic enhancing-memory effect of D-serine and RU360, a mitochondrial calcium uniporter blocker in rat model of Alzheimer's disease.

BACKGROUND: Although Amyloid beta (Aß) and N - methyl d- aspartate receptors (NMDARs are involved in Ca2+ neurotoxicity, the function of mitochondrial calcium uniporter in cognition deficit remain uncertain. Here, we examined the effect of mitochondrial calcium uniporter (MCU) blocker, together with NMDA receptor agonist d-cycloserine (DCS) on memory impairment in a rat model of AD. METHODS: Forty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intracerebroventricular (ICV) injection of Aß1-42 (5 µg /8 µl/rat). Then animals were divided into 5 groups of: Saline + Saline, Aß + Saline, Aß + RU360, Aß + DCS, Aß + RU360 + DCS. Two weeks after the treatments, Morris Water Maze (MWM) and step through passive avoidance learning (SPL) were undertaken for evaluating of spatial and associative memories, respectively. Hippocampal level of cyclic-AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were measured by western blot and ELISA. RESULTS: Co - administration of RU360 and DCS significantly improved both acquisition and retrieval of spatial memory as evident by decreased escape latency and increased time spent in the target quadrant (TTS) in MWM, together with increase in step-through latency, but reduced time spent in the dark compartment in SPL. Furthermore, there was a significant rise in the hippocampal level of CREB and BDNF in comparison with Aß + Saline. CONCLUSION: The present study supports the idea that co- administration of RU360 and DCS ameliorate memory impairment induced by Aß 1-42 probably via CREB / BDNF signaling.