Activation of α7 nAChR by PNU-282987 improves synaptic and cognitive functions through restoring the expression of synaptic-associated proteins and the CaM-CaMKII-CREB signaling pathway

Wang, Xiaoling; Deng, Yuxin; Gao, Yumei; Dong, Yang-Ting; Wang, Fan; Guan, Zhi‐Zhong; Hong, Wei; Qi, Xiaolan

doi:10.18632/aging.102640

Cited by 34 publications

(22 citation statements)

References 50 publications

(65 reference statements)

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“…However, the A-582941 treatment did not ameliorate AD-associated changes, such as Aβ deposits, tau phosphorylation, and the presence of inflammatory cells. In contrast, Wang X. L. et al (2020) activated α7 nAChR in primary hippocampal cells and in a APPswe/PSEN1dE9 double-transgenic AD mouse model with PNU-282987. The activation of α7 nAChR improved the cognitive abilities of mice and, among others, reduced the deposition of Aβ in the hippocampus.…”

Section: Therapeutic Applicationsmentioning

confidence: 86%

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Gąsiorowska

Wydrych

Drapich

et al. 2021

Front. Aging Neurosci.

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The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

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Section: Therapeutic Applicationsmentioning

confidence: 86%

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Gąsiorowska

Wydrych

Drapich

et al. 2021

Front. Aging Neurosci.

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“…These observations indicated that α7 nAChR may also prevent the loss of synaptic proteins caused by Aβ in vivo . It has been previously reported that the inhibition of the expression levels of α7 nAChR in SH-SY5Y cells by RNA interference increases the toxicity and expression levels of Aβ, which subsequently elevates the expression levels of β-site APP-cleaving enzyme 1 (BACE1) and decreases the expression levels of BACE2 ( 38 , 55 ). In the present study, the expression levels of synaptic proteins were reduced to a greater extent by Aβ in the presence of α7 nAChR silencing, which may be related to the reduced production of Aβ caused by α7 nAChR.…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic human Aβ 1-42 was suspended in pre-cooled HFIP at a final concentration of 1 mM; the solution was incubated at room temperature for 60 min and subsequently on ice for 10 min ( 38 ). Aliquots were transferred into non-siliconized microcentrifuge tubes and the HFIP was allowed to evaporate overnight in a hood at room temperature, which was then stored at −80°C ( 38 ). Prior to the treatment of cells, Aβ 1-42 was dissolved in DMSO to obtain a final concentration of 5 mmol/l.…”

Section: Methodsmentioning

confidence: 99%

Expression levels of the α7 nicotinic acetylcholine receptor in the brains of patients with Alzheimer's disease and their effect on synaptic proteins in SH-SY5Y cells

et al. 2020

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Alzheimer's disease (AD) is a chronic neurodegenerative, and abnormal aggregation of the neurotoxic β amyloid (Aβ) peptide is an early event in AD. The present study aimed to determine the correlation between the nicotinic acetylcholine receptor α7 subunit (α7 nAChR) and Aβ in the brains of patients with AD, and to investigate whether the increased expression levels of the α7 nAChR could alter the neurotoxicity of Aβ. The expression levels of α7 nAChR and Aβ in the brains of patients with AD and healthy brains were analyzed using immunofluorescence. Moreover, SH-SY5Y cells were used to stably overexpress or silence α7 nAChR expression levels, prior to the treatment with or without 1 µmol/l Aβ 1-42 oligomer (AβO). The mRNA and protein expression levels of α7 nAChR, synaptophysin (SYP), postsynaptic density of 95 kDa (PSD-95) and synaptosomal-associated protein of 25 kDa (SNAP-25) were subsequently analyzed using reverse transcription-quantitative PCR and western blotting. In addition, the concentration of acetylcholine (ACh) and the activity of acetylcholinesterase (AChE) were analyzed using spectrophotometry, while the cell apoptotic rate was determined using flow cytometry. The expression of Aβ in the brains of patients with AD was found to be significantly increased, whereas the expression of α7 nAChR was significantly decreased compared with the healthy control group. In vitro , the expression levels of α7 nAChR were significantly increased or decreased following the overexpression or silencing of the gene, respectively. Consistent with these observations, the mRNA and protein expression levels of SYP, PSD-95 and SNAP-25 were also significantly increased following the overexpression of α7 nAChR and decreased following the genetic silencing of the receptor. In untransfected or negative control cells, the expression levels of these factors and the apoptotic rate were significantly reduced following the exposure to AβO, which was found to be attenuated by α7 nAChR overexpression, but potentiated by α7 nAChR RNA silencing. However, no significant differences were observed in either the ACh concentration or AChE activity following transfection. Collectively, these findings suggested that α7 nAChR may protect the brains of patients with AD against Aβ, as α7 nAChR overexpression increased the expression levels of SYP, SNAP-25 and PSD-95, and attenuated the inhibitory effect of Aβ on the expression of these synaptic proteins and cell apoptosis. Overall, this indicated that α7 nAChR may serve an important neuroprotective role in AD.

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“…Synaptic plasticity has long been considered as the neurobiological basis of cognition [ 149 ]. Synaptic plasticity also plays an essential role in VaD.…”

Section: Restoration Of Synaptic Plasticitymentioning

confidence: 99%

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective

Kuang¹,

Zhou²,

Zhu³

et al. 2021

Aging and disease

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Activation of α7 nAChR by PNU-282987 improves synaptic and cognitive functions through restoring the expression of synaptic-associated proteins and the CaM-CaMKII-CREB signaling pathway

Cited by 34 publications

References 50 publications

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Expression levels of the α7 nicotinic acetylcholine receptor in the brains of patients with Alzheimer's disease and their effect on synaptic proteins in SH-SY5Y cells

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective

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