Potassium channels in the neuronal homeostasis and neurodegenerative pathways underlying Alzheimer’s disease: An update

Highlights

• Potassium (K⁺) channels are key regulators of cell excitability in several tissues.

• A dysregulation of K⁺ channels is associated with Alzheimer’s disease (AD).

• The role of K⁺ channels in AD is not completely elucidated.

• Understanding their functions will be helpful for clarifying AD pathogenesis.

• Modulating K⁺ channel expression should be useful for developing novel drugs.

Abstract

With more than 80 subunits, potassium (K⁺) channels represent a group of ion channels showing high degree of diversity and ubiquity. They play important role in the control of membrane depolarization and cell excitability in several tissues, including the brain. Controlling the intracellular and extracellular K⁺ flow in cells, they also modulate the hormone and neurotransmitter release, apoptosis and cell proliferation. It is therefore not surprising that an improper functioning of K⁺ channels in neurons has been associated with pathophysiology of a wide range of neurological disorders, especially Alzheimer’s disease (AD).

This review aims to give a comprehensive overview of the basic properties and pathophysiological functions of the main classes of K⁺ channels in the context of disease processes, also discussing the progress, challenges and opportunities to develop drugs targeting these channels as potential pharmacological approach for AD treatment.

Introduction

Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disorder with a complex etiology and represents the most prevalent form of dementia in elderly individuals (Crous-Bou et al., 2017). The major risk factor for AD is represented by aging, the inevitable degenerative physiological process which results in a progressive functional and structural decline, from the cellular level to the whole body, causing a reduced ability to adapt to environmental changes and stressors as well as the accumulation of misfolded proteins (Mecocci et al., 2018). AD has been characterized by the neuropathological hallmarks of extracellular senile plaques constituted by the amyloid-β (Aβ) peptide and intracellular paired helical filaments of hyper-phosphorylated microtubule-associated protein tau (Huang and Mucke, 2012). Aβ plaques are generated by sequential proteolytic cleavage of Aβ precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. The extracellular deposition of Aβ in the brain could trigger a cascade of pathological events, including microglia-mediated inflammation, mitochondrial dysfunctions, excess in mitochondrial reactive oxygen species (ROS) generation and increased oxidative stress, which may represent causative factors of dementia and cell death (Tönnies and Trushina, 2017). Dysfunction of neurotransmission, brain networks and loss of synapses are also involved in AD pathogenesis (Reddy, 2017). In spite of its prevalence, the etiology of the disease remains to be fully elucidated and there are no effective therapeutic strategies to cure AD or inhibit the progression of its symptoms (Mangialasche et al., 2010).

Some evidence reported an emerging role of altered neuronal excitability, finely controlled by different ion channels and their associated proteins, occurring early during AD pathogenesis (Palop et al., 2007; Frazzini et al., 2016). Ion channels are membrane-spanning proteins forming selective pores for sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺) or chloride (Cl⁻) ions (Zaydman et al., 2012). Among them, K⁺ channels are the most numerous and diverse channels present in the mammalian brain. Controlling the intracellular and extracellular flow of K⁺ ions in different cells (e.g., neurons, glia and lymphocytes), they play crucial role as determinant of membrane excitability, setting resting membrane potentials and driving repolarization, becoming target drugs for the treatment of neurodegenerative disorders (Miller, 2000). K⁺ channels might be divided into five structural types depending on the activation modes and the number of transmembrane (TM) segments: 6-TM K⁺ channels (K_V) with voltage gates, 2-TM K⁺ channel (Kir), 2-pore 4-TM K⁺ channels (K2P), Ca²⁺-activated 6-TM or 7-TM K⁺ channels (K_Ca) and the hyperpolarization-activated cyclic nucleotide-gated (HCN). It appears that K⁺ channels are naturally subjected to oxidation by ROS in both aging and neurodegenerative conditions characterized by high levels of ROS (Sesti, 2016). A dysfunction of K⁺ channels has been observed in fibroblasts (Etcheberrigaray et al., 1993) and platelets (de Silva et al., 1998) of AD patients. Post-mortem studies have also reported an alteration in K⁺ channels expression in AD brains (Ikeda et al., 1991). Moreover, it has been demonstrated that Aβ is not only involved in the AD pathogenesis, but it is also a modulator of K⁺ channel activity (Plant et al., 2005) and may have a physiological role in controlling neuronal excitability (Ramsden et al., 2002).

In this review, we report an updated discussion on the most prominent K⁺ channels involved in the pathophysiology of AD, that are summarized in Table 1.