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

• Published in: Frontiers in cellular neuroscience Vol. 16; p. 868842
• Main Authors: Revuelta, Miren, Urrutia, Janire, Villarroel, Alvaro, Casis, Oscar
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 21-04-2022; Frontiers Media S.A
• Subjects: Alzheimer's disease; Animal models; Brain; Brain-derived neurotrophic factor; CD163 antigen; Cell activation; Cell culture; Cell differentiation; Cell division; Cell proliferation; Chemokines; Cytokines; Cytotoxicity; Extracellular matrix; Free radicals; Genotype & phenotype; Gliosis; Homeostasis; IL-1β; Inflammation; Insulin-like growth factor I; Kinases; KV1.3; Microglia; neural stem cell (NSC); Neural stem cells; neurodegenaration; Neurodegenerative diseases; Neuroscience; Neurotoxicity; NF-κB protein; Nitric oxide; Peptides; Phagocytes; Potassium channels (voltage-gated); Proteins; Stem cell transplantation; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2022.868842

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-1
β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase K
V
1.3 channels expression, protein levels and current density. Several studies highlight the importance of K
V
1.3 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
V
1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines
IL-1
β and
TNF-
α through the NF-kB and p38MAPK pathway. Overall, we conclude that K
V
1.3 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.