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.

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Cav2.2 channels are key regulators of presynaptic Ca2+ influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer’s disease (AD) is less clear. In this short communication, we show that recombinant hCav2.2/b1b/a2d1 channels are modulated by human synthetic AD-related protofibrillar amyloid beta Ab1-42 peptides. Structural studies revealed a time-dependent increase in protofibril length, with the majority of protofibrils less than 100 nm at 24 h, while at 48 h, the majority were longer than 100 nm. Cav2.2 modulation by Ab1-42 was different between a ‘low’ (100 nM) and ‘high’ (1 µM) concentration in terms of distinct effects on individual biophysical parameters. A concentration of 100 nM Ab1-42 caused no significant changes in the measured biophysical properties of Cav2.2 currents. In contrast, 1 µM Ab1-42 caused an inhibitory decrease in the current density (pA/pF) and maximum conductance (Gmax), and a depolarizing shift in the slope factor (k). These data highlight a differential modulation of Cav2.2 channels by the Ab1-42 peptide. Discrete changes in the presynaptic Ca2+ flux have been reported to occur at an early stage of AD; therefore, this study reveals a potential mechanistic link between amyloid accumulation and Cav2.2 channel modulation.

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