Ciccone, Roselia
(2016)
Critical role of KV3.4 Potassium Channel in Aβ oligomers effects on neuron excitability, astrocytes activation and cognitive functions in Alzheimer’s Disease.
[Tesi di dottorato]
Item Type: |
Tesi di dottorato
|
Resource language: |
English |
Title: |
Critical role of KV3.4 Potassium Channel in Aβ oligomers effects on neuron excitability, astrocytes activation and cognitive functions in Alzheimer’s Disease |
Creators: |
Creators | Email |
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Ciccone, Roselia | rosy.ciccone@alice.it |
|
Date: |
31 March 2016 |
Number of Pages: |
136 |
Institution: |
Università degli Studi di Napoli Federico II |
Department: |
Neuroscienze e Scienze Riproduttive ed Odontostomatologiche |
Scuola di dottorato: |
Medicina molecolare |
Dottorato: |
Neuroscienze |
Ciclo di dottorato: |
28 |
Coordinatore del Corso di dottorato: |
nome | email |
---|
Annunziato, Lucio | lannunzi@unina.it |
|
Tutor: |
nome | email |
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Pannaccione, Anna | UNSPECIFIED |
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Date: |
31 March 2016 |
Number of Pages: |
136 |
Keywords: |
Alzheimer's Disease, Kv3.4, Tg2576 mouse model |
Settori scientifico-disciplinari del MIUR: |
Area 05 - Scienze biologiche > BIO/14 - Farmacologia |
[error in script]
[error in script]
Date Deposited: |
11 Apr 2016 12:41 |
Last Modified: |
21 Apr 2019 01:00 |
URI: |
http://www.fedoa.unina.it/id/eprint/11009 |
Collection description
Voltage gated potassium channels (KV) play a pathogenetic role in many neurodegenerative disorders, including Alzheimer’s Disease (AD). Recently, it has been demonstrated that hippocampal neurons and NGF-differentiated PC-12 cells exposed to Aβ1–42 display a selective over-expression and increased activity of KV3.4 potassium channels. The goal of this study has been to further investigate the role of KV3.4 channels in a transgenic mouse model of AD, Tg2576. Firstly, we observed an over-expression of KV3.4 and its accessory subunit MiRP2 in the hippocampus of young Tg2576 mice (3 months old), whereas no significant modification was observed in elderly Tg2576 mice (14-18 months old). Moreover, Tg2576 hippocampal neurons showed an early increase in KV3.4 channel activity These data suggested that KV3.4 up-regulation play a critical role in the early stages of AD, since it contributes to neuronal hyperexcitability induced by the accumulation of Aβ1-42 dimers and trimers occurring in these stages. The immunocytochemical analysis showed that the early increase in KV3.4 expression was accompanied by an altered subcellular distribution of this protein in Tg2576 hippocampal neurons, in particular we observed a more intense KV3.4 immunosignal localized to the soma plasma membrane. Intriguingly, the over-expression and increase activity of KV3.4 in young Tg2576 mice were accompanied by the activation of caspase-3. Moreover, the KV3.4 silencing in vivo by intracerebroventricular injection, not only strongly reduced KV3.4 expression but also prevented caspase-3 activation. Interestingly, siKV3.4 reduced the Aβ1-42 trimers levels in the same young Tg2576 mice suggesting the possible indirect link between KV3.4 over-expression, caspases activation and Aβ1-42 trimers deposition. Several studies showed that Aβ1-42 trimers are closely related to memory impairment occurring in the early stages of AD. Our studies performed by T-maze spontaneous alternation test indicated that Tg2576 mice (3 months old) exhibited the impairment of exploration ability, spatial learning and memory abilities. Interestingly, Tg2576 mice in the presence of siKV3.4 displayed the amelioration in exploration ability and memory performance. Furthermore, the Open Field test showed that Tg2576 mice (3 months old) were hyperactive since they travelled a greater average distance compared to Wild Type mice. Attractively, Tg2576 in the presence of siKV3.4 displayed a reduction in the distance traveled compared to Tg2576 mice in the absence of siKV3.4. Collectively, these data proposed that the inhibition of KV3.4, ameliorating memory performance and non-cognitive symptoms, could become a new pharmacological target in the care of AD. To this aim we tested a new synthetic compound, BDS1-8, containing the first eight aminoacids from full lenght BDS-I, a well known KV3.4 inhibitor. BDS1-8 was able to prevent both increased KV3.4 activity and caspase-3 activation induced by Aβ1–42 oligomers. At last, we observed an up-regulation of KV3.4 and GFAP protein expression in primary astrocytes exposed to Aβ1-42 peptide. Interestingly, coexpression and co-immunoprecipitation studies revealed a large overlap and a direct binding of KV3.4 with GFAP. Moreover, the in vivo siKV3.4 significantly down-regulated GFAP in Tg2576 mice (3 months old) confirmig the closely link between GFAP and KV3.4. These data suggested that GFAP might promote channel trafficking in precise membrane domains faciliting the accumulation of KV3.4 channel, in order to modulate cellular mechanisms mediated by K+ ions. Collectively, our data suggest a critical role of KV3.4 in Aβ oligomers effects on neuron excitability, astrocytes activation and cognitive functions in AD.
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