Abstract
Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer’s disease (AD). Chronic neuroinflammation results in diminished synaptic plasticity and loss of GluN1 N-methyl-D-aspartate (NMDA) receptors in the hippocampus, leading to the cognitive deficits that are the most common symptoms of AD. Therefore, it is suggested that chronic inflammation may alter expression levels of GluN2A and GluN2B subunits of NMDA receptors and associated intracellular signalling. Chronic neuroinflammation was induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle in Fischer-344 rats. The status of hippocampus-dependent memory was evaluated in control rats and rats chronically infused with LPS. Microglial activation in the hippocampus was examined using immunohistochemical staining. Western blot analysis was used to measure membrane levels of GluN2A and GluN2B subunits of NMDA receptors and mitogen-activated protein kinase (MAPK) in the hippocampi of these rats, and immunofluorescent double labeling was used to assess the cellular location of MAPK. Microglial activation was observed in the hippocampi of rats that showed memory impairments with chronic LPS infusion. Chronic LPS infusion reduced the levels of GluN2A and GluN2B and increased the levels of phosphorylated MAPKs in the hippocampus. MAPK-positive immunoreactivity was observed mostly in the neurons and also in non-neuronal cells. Reductions in GluN2A and GluN2B subunits of NMDA receptors coupled with altered MAPK signaling, in response to inflammatory stimuli may be related to the cognitive deficits observed in AD.
Highlights
Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer’s disease (AD) [1,2,3,4,5]
Voltage-dependent calcium channel dependent-long-term potentiation (LTP) and NMDA receptor (NMDAR)-dependent LTP has been attenuated [13] as well as long-term depression (LTD) has been impaired [14] in Schaffer collateral-cornu ammonis 1 (CA1) synapses in the hippocampus of rats chronically infused with LPS
Rats chronically infused with LPS showed hippocampusdependent spatial memory impairments in the Morris water maze task and microglial activation in the hippocampus
Summary
Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer’s disease (AD) [1,2,3,4,5]. It has been demonstrated that brain inflammation leads to a decrease in the number of GluN1 N-methyl-Daspartate receptors (NMDARs) within the dentate gyrus (DG) and cornu ammonis 3 (CA3) hippocampal areas, without any loss of neurons [10]. NMDA receptor (NMDAR)-dependent LTP has been attenuated [13] as well as LTD has been impaired [14] in Schaffer collateral-cornu ammonis 1 (CA1) synapses in the hippocampus of rats chronically infused with LPS. The present experiment was conducted to evaluate the effects of chronic LPS infusion on the expression levels of GluN2A and GluN2B subunits of NMDARs and its associated Erk and p38 signaling. Levels of p-Erk1/2 and phosphorylated p38 (p-p38) were increased in the hippocampus of chronically LPS-infused rats, and these immunoreactivities were observed mostly in neurons and in non-neuronal cells in the hippocampi of LPSinfused rats
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