Abstract
Ligands of nicotinic acetylcholine receptors (nAChRs) are widely considered as potential therapeutic agents. The present study used primary hippocampus cells and APPswe/PSEN1dE9 double-transgenic mice models to study the possible therapeutic effect and underlying mechanism of the specific activation of α7 nAChR by PNU-282987 in the pathogenesis of Alzheimer’s disease. The results indicated that activation of α7 nAChR attenuated the Aβ-induced cell apoptosis, decreased the deposition of Aβ, increased the expression of synaptic-associated proteins, and maintained synaptic morphology. Furthermore, in the APP/PS1_DT mice model, activation of α7 nAChR attenuated Aβ-induced synaptic loss, reduced the deposition of Aβ in the hippocampus, maintained the integral structure of hippocampus-derived synapse, and activated the calmodulin (CaM)-calmodulin-dependent protein kinase II (CaMKII)-cAMP response element-binding protein signaling pathway by upregulation of its key signaling proteins. In addition, activation of α7 nAChR improved the learning and memory abilities of the APP/PS1_DT mice. Collectively, the activation of α7 nAChR by PNU-282987 attenuated the toxic effect of Aβ in vivo and in vitro, which including reduced deposition of Aβ in the hippocampus, maintained synaptic morphology by partially reversing the expression levels of synaptic-associated proteins, activation of the Ca2+ signaling pathway, and improvement of the cognitive abilities of APP/PS1_DT mice.
Highlights
Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder
The results demonstrated that the apoptosis rate of amyloid β (Aβ) oligomer and MLA-treated primary neuronal cells was significantly increased compared with the control group
To examine whether activation of α7 neuronal nicotinic acetylcholine receptor (nAChR) by PNU282987 alleviates the cognitive deficits in amyloid precursor protein (APP)/PS1_DT mice, the present study measured the potential of α7 nAChR to alleviate AD-induced declines in spatial memory and learning ability by using the Morris water maze [10]
Summary
The main clinical manifestations of AD patients are progressive memory decline, abnormal brain function and a decline in social adaptability. The pathological features of AD include the formation of extracellular senile plaques (SPs), intraneuronal neurofibrillary tangles aggregating of hyperphosphorylated tau protein and the loss of neurons [1]. SPs mainly consist of extracellular amyloid β (Aβ), which contains 38-43 amino acids and plays a key role in the pathogenesis of AD [2]. Deposition of Aβ in the human brain is considered to be associated with crosssectional synaptic network dysfunction, progressive brain atrophy, an imbalance in neuronal calcium homeostasis and longitudinal cognitive decline [3]. Investigating methods to prevent the toxic effects of Aβ could be one of the promising strategies of treating AD patients
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