Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer’s disease mouse model

Frazzini, Valério; Guarnieri, Simone; Bomba, Manuela; Navarra, Riccardo; Morabito, Caterina; Mariggiò, Maria A.; Sensi, Stefano L.

doi:10.1038/cddis.2016.18

Cited by 86 publications

(64 citation statements)

References 40 publications

(50 reference statements)

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“…The involvement of Fyn is consistent with the prominent role of this kinase in TBI and Alzheimer's disease, two conditions associated with robust KCNB1 oxidation. 8, 9, 17, 25, 26 The amounts of phosphorylated Fyn and Src were comparable, but the proteins were detected by different antibodies and therefore the involvement of other Src family members in the apoptotic pathway activated by oxidation of KCNB1 cannot be ruled out.…”

Section: Discussionmentioning

confidence: 97%

Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain

Gowda

Sharad

et al. 2017

Cell Death Dis

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Oxidative modification of the voltage-gated potassium (K+) channel KCNB1 promotes apoptosis in the neurons of cortex and hippocampus through a signaling pathway mediated by Src tyrosine kinases. How oxidation of the channel is transduced into Src recruitment and activation, however, was not known. Here we show that the apoptotic signal originates from integrins, which form macromolecular complexes with KCNB1 channels. The initial stimulus is transduced to Fyn and possibly other Src family members by focal adhesion kinase (FAK). Thus KCNB1 and integrin alpha chain V (integrin-α5) coimmunoprecipitated in the mouse brain and these interactions were retained upon channel's oxidation. Pharmacological inhibition of integrin signaling or FAK suppressed apoptosis induced by oxidation of KCNB1, as well as FAK and Src/Fyn activation. Most importantly, the activation of the integrin–FAK–Src/Fyn cascade was negligible in the presence of non-oxidizable C73A KCNB1 mutant channels, even though they normally interacted with integrin-α5. This leads us to conclude that the transition between the non-oxidized and oxidized state of KCNB1 activates integrin signaling. KCNB1 oxidation may favor integrin clustering, thereby facilitating the recruitment and activation of FAK and Src/Fyn kinases.

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Section: Discussionmentioning

confidence: 97%

Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain

Gowda

Sharad

et al. 2017

Cell Death Dis

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“…In addition, altered K v 2.1 potassium channel function has recently been shown to mediate increased excitability in cultured hippocampal neurons (14–19 days in vitro ) from embryonic day 16–18 triple transgenic mice (Frazzini et al, 2016). To the best of our knowledge, our data constitute the first clear demonstration of higher sensitivity to audiogenic seizures and hippocampal CA3 neuronal network hyperexcitability prior to onset of amyloid plaque deposition, neurofibrillary pathology, and cognitive deficit in this mouse line which carries human APP, tau and PS1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

Kazim

Chuang

Zhao

et al. 2017

Front. Aging Neurosci.

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Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer’s disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aβ precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes Aβ plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aβ antibody and by mGluR5 blockade in 3xTg-AD mice.

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“…In addition, mouse hippocampal neuron and SK-N-MC cells have been widely used as an in vitro neuronal cell model to investigate neuronal pathogenesis of AD26272829. Elucidation of the critical molecules affecting the occurrence of AD under diabetic conditions is important for developing a comprehension of AD pathogenesis and can be helpful in developing novel strategies for treatment and prevention of AD.…”

mentioning

confidence: 99%

High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells

Lee

Ryu

Jung

et al. 2016

Sci Rep

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There is an accumulation of evidence indicating that the risk of Alzheimer’s disease is associated with diabetes mellitus, an indicator of high glucose concentrations in blood plasma. This study investigated the effect of high glucose on BACE1 expression and amyloidogenesis in vivo, and we present details of the mechanism associated with those effects. Our results, using ZLC and ZDF rat models, showed that ZDF rats have high levels of amyloid-beta (Aβ), phosphorylated tau, BACE1, and APP-C99. In vitro result with mouse hippocampal neuron and SK-N-MC, high glucose stimulated Aβ secretion and apoptosis in a dose-dependent manner. In addition, high glucose increased BACE1 and APP-C99 expressions, which were reversed by a reactive oxygen species (ROS) scavenger. Indeed, high glucose increased intracellular ROS levels and HIF-1α expression, associated with regulation of BACE1 and Liver X Receptor α (LXRα). In addition, high glucose induced ATP-binding cassette transporter A1 (ABCA1) down-regulation, was associated with LXR-induced lipid raft reorganization and BACE1 localization on the lipid raft. Furthermore, silencing of BACE1 expression was shown to regulate Aβ secretion and apoptosis of SK-N-MC. In conclusion, high glucose upregulates BACE1 expression and activity through HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization, leading to Aβ production and apoptosis of SK-N-MC.

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Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer’s disease mouse model

Cited by 86 publications

References 40 publications

Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain

Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells

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