Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Abstract

Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase K_V1.3 channels expression, protein levels and current density. Several studies highlight the importance of K_V1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that K_V1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that K_V1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

Keywords: Alzheimer’s disease; KV1.3; inflammation; microglia; neural stem cell (NSC); neurodegenaration; therapeutic targets.

FIGURE 1

Schematic illustration of microglial activation due to Aβ accumulation. Activated microglia polarized into M1 or M2 phenotype. Activation of M1 phenotype induces pro-inflammatory cytokine, chemokine and complement protein release provoking citotoxicity and consequently astrocyte A1 activation, neuroinflammation and neuronal cell death. M2 phenotype activation induces anti-inflammatory response and consequently A2 activation and neuroprotection. K_V1.3 inhibition has been related to M2 phenotype polarization.

FIGURE 2

Microglia activation to M1 and the K_V1.3 blockade effect on this activation. (A) Different stimuli activate microglia to pro-inflammatory state (M1). The activation of the NF-κB pathway induced an increase of K_V1.3 protein in the membrane, among others effects. (B) K_V1.3 inhibitor provokes a smaller Ca²⁺ entry reducing secretion of pro-inflammatory factors due to the decrease in the activation of NF-κB pathway. P2 × 7 and P2 × 4, purinergic receptors; TLR4, toll like receptor 4; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PAMPs, exposure to pathogen-associated molecular patterns; DAMPs, endogenous damage-associated molecular patterns; ROS, reactive oxygen species; Fyn, non-receptor tyrosine-protein kinase; IL, interleukin; TNF, tumor necrosis factor; iNOS, nitric oxide synthase, NO, nitric oxide.