Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits. Two hallmarks of AD that cause chronic inflammation and lead to neuronal dysfunction and damage are tau tangles and amyloid plaques. Microglial cells, the primary immune cells of the central nervous system, maintain a homeostatic active/inactive state via a bidirectional, dynamic communication with neurons. Several studies have revealed that dysregulated microglial activation leads to AD pathology. Therefore, we reviewed the relationship between AD and two important signaling complexes, CX3 chemokine ligand 1 (CX3CL1)/CX3CR1 and ATP/P2X7R, that play critical roles in the regulation of microglial activation. CX3CL1/CX3CR1 is one important signaling which controls the microglia function. Altering this pathway can have opposite effects on amyloid and tau pathology in AD. Another important molecule is P2X7R which involves in the activation of microglia. Over activation of P2X7R is evident in AD pathogenesis. In this review, we discuss influence of the two signaling pathways at different stages of AD pathology as well as the drug candidates that can modulate CX3CL1/CX3CR1 and ATP/P2X7R.

The genetic and molecular basis underlying fear memory formation is a key theme in anxiety disorder research. Because activating transcription factor 3 (ATF3) is induced under stress conditions and is highly expressed in the hippocampus, we hypothesise that ATF3 plays a role in fear memory formation. We used fear conditioning and various other paradigms to test Atf3 knockout mice and study the role of ATF3 in processing fear memory. The results demonstrated that the lack of ATF3 specifically enhanced the expression of fear memory, which was indicated by a higher incidence of the freeze response after fear conditioning, whereas the occurrence of spatial memory including Morris Water Maze and radial arm maze remained unchanged. The enhanced freezing behaviour and normal spatial memory of the Atf3 knockout mice resembles the fear response and numbing symptoms often exhibited by patients affected with posttraumatic stress disorder. Additionally, we determined that after fear conditioning, dendritic spine density was increased, and expression of Gelsolin, the gene encoding a severing protein for actin polymerisation, was down-regulated in the bilateral hippocampi of the Atf3 knockout mice. Taken together, our results suggest that ATF3 may suppress fear memory formation in mice directly or indirectly through mechanisms involving modulation of actin polymerisation.

Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemicPrdx6knockout (Prdx6^−/−) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mousePrdx6into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus ofPrdx6^−/−mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.

Peroxiredoxin 6 (PRDX6) is expressed dominantly in the astrocytes and exerts either neuroprotective or neurotoxic effects in the brain. Although PRDX6 can modulate several signaling cascades involving cognitive functions, its physiological role in spatial memory has not been investigated yet. This study aims to explore the function of the Prdx6 gene in spatial memory formation and synaptic plasticity. We first tested Prdx6 −/− mice on a Morris water maze task and found that their memory performance was defective, along with reduced long-term potentiation (LTP) in CA3-CA1 hippocampal synapses recorded from hippocampal sections of home-caged mice. Surprisingly, after the probe test, these knockout mice exhibited elevated hippocampal LTP, higher phosphorylated ERK1/2 level, and decreased reactive astrocyte markers. We further reduced ERK1/2 phosphorylation by administering MEK inhibitor, U0126, into Prdx6 −/− mice before the probe test, which reversed their spatial memory deficit. This study is the first one to report the role of PRDX6 in spatial memory and synaptic plasticity. Our results revealed that PRDX6 is necessary for maintaining spatial memory by modulating ERK1/2 phosphorylation and astrocyte activation.

Peroxiredoxin 6 (PRDX6) is expressed throughout the brain, including the hippocampus, where it plays a potential role in synaptic regulation and forming emotional and spatial memories. PRDX6 is predominantly detected in the female mouse’s hippocampus; thus, we investigate the effect of the Prdx6 gene on behavioral phenotypes and synaptic functions using female Prdx6 knockout (Prdx6^−/−) mice. Our results demonstrate that female Prdx6^−/− mice exhibited anxiety-like behavior, enhanced contextual fear memory, and impaired spatial memory. We also found increased, paired–pulse facilitation ratios, and decreased long-term potentiation (LTP) in the hippocampal region of these female Prdx6^−/− mice. The present study helps to understand better the PRDX6’s role in emotional response and spatial memory formation in female mice.