title: The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer's Disease.
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-βin vitro. In the present study, we investigated the contribution of KCa3.1 channels to astrogliosis-mediated neuroinflammation, using TgAPP/PS1mice 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/PS1mice 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 neuronsin vitrovia activation of JNK and ROS.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Mengni
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
keywords: Alzheimer’s disease; GFAP; astrogliosis; inflammation; neurons