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?? and ?1 Integrins mediate A?-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

ABSTRACT: ?? and ?1 integrins mediate A?-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 µg/mL 17E6 and 5 µg/mL ab58524, which are specific ?? and ?1 integrin antagonists, respectively, for 42 h prior to 10 µM A? treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 µg/mL polybrene. Under these conditions, the neurons were transfected and the apoptosis of different cell types was detected. Moreover, we used real-time PCR and Western blotting analyses to detect the expression of FAK and ?FAK genes in different cell types and investigated the underlying mechanism and signal pathway by which ?? and ?1 integrins mediate A?-induced neurotoxicity in hippocampal neurons. An MTT assay showed that both 17E6 and ab58524 significantly increased cell viability compared with the A?-treated neurons (P<0.01 and P<0.05, respectively). However, this protective effect was markedly attenuated after transfection with silencing FAK (siFAK). Moreover, TUNEL immunostaining and flow cytometry indicated that both 17E6 and ab58524 significantly protected hippocampal neurons against apoptosis induced by A? (P<0.05) compared with the A?-treated cells. However, this protective effect was reversed with siFAK treatment. Both the gene and protein expression of FAK increased after A? treatment. Interestingly, as the gene and protein levels of FAK decreased, the ?FAK protein expression markedly increased. Furthermore, both the gene and protein expression of FAK and ?FAK were significantly diminished. Thus, we concluded that both ?? and ?1 integrins interfered with A?-induced neurotoxicity in hippocampal neurons and that this mechanism partially contributes to the activation of the Integrin-FAK signaling pathway.

SUBMITTER: Han HY

PROVIDER: S-EPMC3670848 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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αν and β1 Integrins mediate Aβ-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

Han Hai-Yan HY Zhang Jin-Ping JP Ji Su-Qiong SQ Liang Qi-Ming QM Kang Hui-Cong HC Tang Rong-Hua RH Zhu Sui-Qiang SQ Xue Zheng Z

PloS one 20130603 6

αν and β1 integrins mediate Aβ-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 µg/mL 17E6 and 5 µg/mL ab58524, which are specific αν and β1 integrin antagonists, respectively, for 42 h prior to 10 µM Aβ treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 µg/mL polybrene. Under these ...[more]

PMID: 23755149

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Project description:Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (?R), one of the major opioid receptors, strongly influences memory processing in that alterations in ?R signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether ?R signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective ?R depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal ?R signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal ?Rs were significantly activated during acute stress. Blockage of hippocampal ?Rs, non-selective deletion of ?Rs or selective deletion of ?Rs on GABAergic neurons (?RGABA) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a ?RGABA-dependent manner. Pharmaceutically enhancing hippocampal GABAA receptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate ?RGABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.

Dataset Information

?? and ?1 Integrins mediate A?-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

Publications

αν and β1 Integrins mediate Aβ-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

Similar Datasets

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