Microglia in Alzheimer's Disease: A Role for Ion Channels

Abstract

Alzheimer's disease is the most common form of dementia, it is estimated to affect over 40 million people worldwide. Classically, the disease has been characterized by the neuropathological hallmarks of aggregated extracellular amyloid-β and intracellular paired helical filaments of hyperphosphorylated tau. A wealth of evidence indicates a pivotal role for the innate immune system, such as microglia, and inflammation in the pathology of Alzheimer's disease. The over production and aggregation of Alzheimer's associated proteins results in chronic inflammation and disrupts microglial clearance of these depositions. Despite being non-excitable, microglia express a diverse array of ion channels which shape their physiological functions. In support of this, there is a growing body of evidence pointing to the involvement of microglial ion channels contributing to neurodegenerative diseases such as Alzheimer's disease. In this review, we discuss the evidence for an array of microglia ion channels and their importance in modulating microglial homeostasis and how this process could be disrupted in Alzheimer's disease. One promising avenue for assessing the role that microglia play in the initiation and progression of Alzheimer's disease is through using induced pluripotent stem cell derived microglia. Here, we examine what is already understood in terms of the molecular underpinnings of inflammation in Alzheimer's disease, and the utility that inducible pluripotent stem cell derived microglia may have to advance this knowledge. We outline the variability that occurs between the use of animal and human models with regards to the importance of microglial ion channels in generating a relevant functional model of brain inflammation. Overcoming these hurdles will be pivotal in order to develop new drug targets and progress our understanding of the pathological mechanisms involved in Alzheimer's disease.

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

“…Homeostatic microglia are considered to be in a sensing state 15 , equipped to detect environmental changes in order to respond to a variety of stimuli. At the center of this transformation is identification of several surface channels and receptors that are critical for entry of calcium ions 16,17 . Thus, PWK are predicted to be a novel strain in which to understand differences related to this process.…”

Data-Driven Analysis of Age, Sex, and Tissue Effects on Gene Expression Variability in Alzheimer's Disease

“…In general, as potassium channels open to increase potassium in the cells, calcium is decreased by inhibiting the Ca 2+ gated channels (Padgett and Slesinger, 2010). Increased activity of the potassium channels, especially the voltage-gated channels have been associated with regulating microglia function and priming which in turn leads to increased ROS production in AD (Rangaraju et al, 2015; Thei et al, 2018).…”

Folate-Dependent Cognitive Impairment Associated With Specific Gene Networks in the Adult Mouse Hippocampus

“…Similarly, ion channels have been generally implicated in AD, so our ion-channel ontological category genes may present specific targets for nutrition-related cognitive decline (54). Mcoln1 (a.k.a.…”

“…Perhaps a more interesting ontological category is the 11 downregulated genes associated with MAPK signaling pathway, a number of which (Arrb2, Cacna1g, Fgfr4, Taok1, Cacna1h) have been implicated in Alzheimer's disease (AD) (49)(50)(51)(52)(53). Additionally, two downregulated ontological categories involve ion channel activity, which has also recently been implicated in AD (54).…”