The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer's Disease.

Tianjiao Wei,Lina Hou,Zhihua Yu,Wen Gu,Mengni Yi,Hongzhuan Chen,Qin Lu

doi:10.3389/fphar.2016.00528

Tianjiao Wei, Lina Hou + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2016.00528

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function. Astrogliosis plays a critical role in AD by instigating neuroinflammation, which leads ultimately to cognition decline. We previously showed that the intermediate-conductance Ca2+-activated potassium channel (KCa3.1) is involved in astrogliosis-induced by TGF-β in vitro. In the present study, we investigated the contribution of KCa3.1 channels to astrogliosis-mediated neuroinflammation, using TgAPP/PS1 mice as a model for AD. We found that KCa3.1 expression was increased in reactive astrocytes as well as in neurons in the brains of both TgAPP/PS1 mice and AD patients. Pharmacological blockade of KCa3.1 significantly reduced astrogliosis, microglial activation, neuronal loss, and memory deficits. KCa3.1 blockade inhibited astrocyte activation and reduced brain levels of IL-1β, TNF-α, iNOS, and COX-2. Furthermore, we used primary co-cultures of cortical neurons and astrocytes to demonstrate an important role for KCa3.1 in the process of astrogliosis-induced neuroinflammatory responses during amyloid-β (Aβ)-induced neuronal loss. KCa3.1 was found to be involved in the Aβ-induced activated biochemical profile of reactive astrocytes, which included activation of JNK MAPK and production of reactive oxygen species. Pharmacological blockade of KCa3.1 attenuated Aβ-induced reactive astrocytes and indirect, astrogliosis-mediated damage to neurons. Our data clearly indicate a role for astrogliosis in AD pathogenesis and suggest that KCa3.1 inhibition might represent a good therapeutic target for the treatment of AD.Highlights:(1) Blockade of KCa3.1 in APP/PS1 transgenic mice attenuated astrogliosis and neuron loss, and an attenuation of memory deficits. (2) Blockade of KCa3.1 attenuated Aβ-induced indirect, astrogliosis-mediated damage to neurons in vitro via activation of JNK and ROS.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function
We recently showed that KCa3.1 expression is increased in both reactive astrocytes and neurons in the brains of senescenceaccelerated mouse prone 8 (SAMP8) mice, a model that is generally used to investigate the mechanisms of agerelated memory deficits (Yi et al, 2016b)
The data presented demonstrate that blockade of KCa3.1 attenuates neuropathology by regulating neuroinflammation in a mouse model of AD and, that prevention of astrogliosis might be a promising strategy for the treatment of AD

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function. The proposed mechanisms of cognitive impairment include synaptic dysfunction triggered by β-amyloid (Aβ), neuronal death, oxidative stress, tau pathology, and glutamate excitotoxicity. It is widely acknowledged that reactive gliosis plays a significant role in the progression of AD. Accumulation of reactive astrocytes and activation of microglia in affected brain regions are apparent in both AD patients and the majority of transgenic rodent models of AD. Garwood et al (2011) reported that reactive astrogliosis is involved in regulating Aβ-induced neurotoxicity and tau phosphorylation. Reactive astrocytes release a variety of cytokines and pro-inflammatory mediators, which activate intracellular signaling pathways including extracellular signalingrelated kinase (ERK), c-Jun N-terminal kinase (JNK), protein kinase C and PI3 kinase (Matos et al, 2008)

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