Effects Of Alpha7 Nicotinic Receptor Activation On Beta Amyloid 25-35 -induced Cognitive Deficits And Underlying Molecular Mechanisms

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive functions and impairment of cholinergic system. All of the world, Alzheimer disease will affect increasing numbers of senior citizen. According to statistics, there are 18 million AD patients now. This number will increase to 90 million in 2050. Without progress in preventing or delaying onset of Alzheimer disease, both the number of people with Alzheimer disease and the proportion of the total population affected will increase substantially. The most initial disruption of cholinergic system in AD is the down-regulation ofα7 subtype nicotinic acetylcholine receptors (α7nAChRs) in the hippocampus and cortex, which correlates well with the severity of cognitive deficits. In particular, the high-affinity binding ofα7nAChR to beta-amyloid (Aβ) not only specifically blocks the responses ofα7nAChR, but also facilitates endocytosis and accumulation of Aβin neuronal cells. Intracerebroventricular infusion of Aβcauses memory deficits and neuronal cell death along withα7nAChR dysfunction. These findings imply that Aβ-induced cognitive deficits may be due to impairedα7nAChRs. We reported that acute exposure of hippocampal slices from Aβ-infused rats to DMXB rescues Aβ-induced impairment of synaptic transmission and LTP induction. But DMXB on Aβ25-35-induced cognitive deficits and underlying molecular mechanisms are not completely understood to date. ObjectiveThe objective of this research was to investigate the effects ofα7nAChRs activation on Aβ-induced deficits in cognitive performance, which would be extremely important in clinical practice of AD. This study further evaluated underlying molecular mechanisms of theα7nAChRs activation against Aβ-induced deficits in cognitive.MethodsIntracerebroventricular (i.c.v.) injection of the"aged"Aβ_25-35 (3nM/mouse) was performed into weighing 20-25g adult male mice. Aβ_25-35 mice received once daily intraperitoneal (i.p.) injection of 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB), a selective agonist ofα7nAChR, during 1-10 days after Aβ_25-35 infusion."Morris"water maze task was observed at 5-10 days after Aβ_25-35 infusion. Using electrophysiological analyses, the synaptic transmission, LTP induction andα7nAChR function in hippocampal CA1 region were examined at 12th day after Aβ_25-35 infusion. Level of ERK1/2 phosphorylation was measured by Western blotting analysis. Neuronal death in hippocampal CA1 region were examined at 11th day after i.c.v Aβ_25-35 (9nM/mouse).Results1. Infusion of the"aged"Aβ_25-35 (3nM/mouse) impaired dose-dependently"Morris"water maze task, induction of LTP, probability of presynaptic glutamate releases and function ofα7nAChR.2. The administration of DMXB could improve dose-dependently Aβ_25-35-induced deficits in acquisition performance in Morris water maze task and performed perfectly in probe trail test as control mice did. The treatment with DMXB protected LTP induction andα7nAChR function in hippocampal CA1 area from Aβ_25-35-impairment.3. High-frequency stimulation (HFS)-induced increase in extracellular signal- regulated kinase (ERK) 1/2 phosphorylation was significantly inhibited in Aβ_25-35-mice. The treatment with DMXB could recover HFS-induced elevation of ERK1/2 activity in Aβ_25-35-mice, whereas it did not significantly affect the level of ERK1/2 phosphorylation induced by HFS in control mice.4. Infusion of the"aged"Aβ_25-35 at high concentration (9nM/mouse) induced the death of pyramidal cells in hippocampal CA1 region and impaired acquisition performance in Morris water maze task. 5. The administration of DMXB could significantly attenuate the loss of pyramidal cells and improve the memory function in Aβ_25-35-mice.Conclusion1. Infusion of the"aged"Aβ_25-35 (3nM/mouse) impaired spatial learning and memory, induction of LTP, probability of presynaptic glutamate releases and function ofα7nAChR.2. The activation ofα7nAChR by the selectiveα7nAChR agonist DMXB ameliorates Aβ_25-35-induced cognitive deficits through protection ofα7nAChR and HFS-induced activation of ERK signaling.3. Theα7nAChR agonist protected the loss of neuronal cells from the Aβ_25-35-induced damage.