Up‐regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease

Angulo, Ester; Noé, Verónique; Casadó, Vicent; Mallol, Josefa; Gómez-Isla, Teresa; Lluı́s, Carmen; Ferrer, Isidre; Ciudad, Carlos J.; Franco, Rafael

doi:10.1111/j.1471-4159.2004.02771.x

Cited by 80 publications

(82 citation statements)

References 38 publications

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“…No effect of bAP on the persistent sodium current, leak current, I h or I M has been reported so far , however, several reports have suggested that bAP may modulate I A . Whereas some reports indicate that bAP promotes I A Ramsden et al, 2001, Angulo et al, 2004, other reports indicate that bAP inhibits such current (Jhamandas et al, 2001, Ye et al, 2003. It is still necessary to determine the effect of bAP on all the currents involved in the generation of subthreshold oscillations and if such effect contributes to network dysfunction.…”

Section: Discussionmentioning

confidence: 94%

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

et al. 2009

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Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 94%

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

et al. 2009

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“…In addition, other experiments have revealed that the protein synthesis inhibitor cycloheximide and the transcriptional inhibitor actinomycin D fully prevent A␤-induced K ϩ currents (Pannaccione et al, 2005). It is interesting that cDNA array analysis has also demonstrated that the K V 3.4 gene is up-regulated in the brain extracts of transgenic mice with the amyloid precursor protein 695 Swedish mutation and in the cerebral cortex of patients in the early and later stages of AD (Angulo et al, 2004).…”

Section: Discussionmentioning

confidence: 96%

Up-Regulation and Increased Activity of K_V3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Pannaccione¹,

Boscia²,

Scorziello³

et al. 2007

Mol Pharmacol

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The aim of the present study was to investigate whether K V 3.4 channel subunits are involved in neuronal death induced by neurotoxic ␤-amyloid peptides (A␤). In particular, to test this hypothesis, three main questions were addressed: 1) whether the A␤ peptide can up-regulate both the transcription/translation and activity of K V 3.4 channel subunit and its accessory subunit, MinK-related peptide 2 (MIRP2); 2) whether the increase in K V 3.4 expression and activity can be mediated by the nuclear factor-B (NF-B) family of transcriptional factors; and 3) whether the specific inhibition of K V 3.4 channel subunit reverts the A␤ peptide-induced neurodegeneration in hippocampal neurons and nerve growth factor (NGF)-differentiated PC-12 cells. We found that A␤ 1-42 treatment induced an increase in K V 3.4 and MIRP2 transcripts and proteins, detected by reverse transcription-polymerase chain reaction and Western blot analysis, respectively, in NGF-differentiated PC-12 cells and hippocampal neurons. Patch-clamp experiments performed in whole-cell configuration revealed that the A␤ peptide caused an increase in I A current amplitude carried by K V 3.4 channel subunits, as revealed by their specific blockade with blood depressing substance-I (BDS-I) in both hippocampal neurons and NGF-differentiated PC-12 cells. The inhibition of NF-B nuclear translocation with the cell membrane-permeable peptide SN-50 prevented the increase in K V 3.4 protein and transcript expression. In addition, the SN-50 peptide was able to block A␤ 1-42 -induced increase in K V 3.4 K ϩ currents and to prevent cell death caused by A␤ 1-42 exposure. Finally, BDS-I produced a similar neuroprotective effect by inhibiting the increase in K V 3.4 expression. As a whole, our data indicate that K V 3.4 channels could be a novel target for Alzheimer's disease pharmacological therapy.

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“…Interestingly, recent works reported changes in Kv3.1 and Kv3.4 expression in neurons and glial cells after betaamyloid treatment (Franciosi et al 2006;Pannaccione et al 2007) and in postmortem brain specimens from Alzheimer's disease (AD) patients (Angulo et al 2004). However, a quantitative evaluation of the expression level of the two Kv3 subunits in distinct brain regions of a mouse model of AD is still lacking.…”

Section: Introductionmentioning

confidence: 98%

Brain Expression of Kv3 Subunits During Development, Adulthood and Aging and in a Murine Model of Alzheimer’s Disease

et al. 2011

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In neurons, voltage-dependent Kv3 potassium channels are essential for the generation of action potentials at high frequency. A dysregulation of the Kv3.1 and Kv3.4 channel subunits has been suggested to contribute to neuronal and glial alterations in Alzheimer's disease, but a quantitative evaluation of these subunits in a mouse model of the pathology is still lacking. We analysed the profile of expression of the four Kv3 subunits by quantitative reverse transcription PCR and Western blot in the whole mouse brain and in dissected brain regions (olfactory bulb, septum, neocortex, hippocampus, brainstem and cerebellum) from 14 days after conception to 18 months after birth. In addition, we measured the levels of Kv3.1 and Kv3.4 messenger RNAs (mRNAs) and proteins in neocortex and hippocampus of APPPS1 mice, a transgenic model of Alzheimer's disease. Although all Kv3 transcripts were significantly expressed in embryonic age in whole brain extracts, only Kv3.1, Kv3.2 and Kv3.4 subunit proteins were present, suggesting a novel role for Kv3 channels at this developmental stage. With the exception of Kv3.4, during postnatal development, Kv3 transcripts and proteins showed a progressive increase in expression and reached an asymptote in adulthood, suggesting that the increase in Kv3 expression during development might contribute to the maturation of the electrical activity of neurons. During aging, Kv3 expression was rather stable. In contrast, in the neocortex of aged APPPS1 mice, Kv3.1 mRNA and protein levels were significantly lower compared to wild type, suggesting that a decrease in Kv3 currents could play a role in the cognitive symptoms of Alzheimer's disease.

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Up‐regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease

Cited by 80 publications

References 38 publications

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Up-Regulation and Increased Activity of K_V3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Brain Expression of Kv3 Subunits During Development, Adulthood and Aging and in a Murine Model of Alzheimer’s Disease

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Up‐regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease

Cited by 80 publications

References 38 publications

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Brain Expression of Kv3 Subunits During Development, Adulthood and Aging and in a Murine Model of Alzheimer’s Disease

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Up-Regulation and Increased Activity of K_V3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death