Premium
Effect of L‐type calcium channel blocking drugs on microglia during inflammation and amyloid pathology
Author(s) -
Hopp Sarah C.,
Wickline Jessica,
Smith Sabrina
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043407
Subject(s) - microglia , neuroprotection , neurotoxicity , calcium in biology , pharmacology , nitric oxide , calcium channel , neuroinflammation , inflammation , in vivo , tumor necrosis factor alpha , medicine , calcium , biology , immunology , microbiology and biotechnology , chemistry , endocrinology , toxicity
Background During Alzheimer’s Disease (AD), microglia accumulate near amyloid plaques where they acquire a non‐homeostatic phenotype, lose essential neuroprotective functions, and take on an “activated’ phenotype that can induce neurotoxicity. Microglia intracellular calcium orchestrates these functions including cytokine production and formation of neurotoxic reactive oxygen species. Notably, other groups have demonstrated that activated, non‐homeostatic microglia in mouse models of AD display dysregulated intracellular calcium that may mediate their dysfunction. Epidemiological evidence suggests that using calcium channel blocker (CCB) drugs is associated with a reduced incidence of neurodegenerative diseases such as AD. However, the mechanism by which CCBs reduce AD risk is currently unknown. We hypothesize that CCBs reduce AD risk via modulation of microglia, the immune cells of the brain. Method Using cultured microglia in vitro, we tested whether CCBs that target L‐type voltage‐dependent calcium channels (L‐VDCCs) could prevent microglia activation in response to lipopolysaccharide (LPS), as measured by cytokine production. We also use the calcium indicator Fluo‐8 to measure directly whether L‐VDCCs could prevent LPS‐induced calcium flux. We then tested whether one of the CCBs, isradipine, could prevent microglia response to LPS in vivo in wild‐type animals. Finally, we used the 5xFAD mouse model of AD to examine whether isradipine could alter microglia phenotype in the presence of amyloid pathology in vivo. Result We found that L‐VDCC antagonist CCBs significantly reduce gene expression of inducible nitric oxide synthetase, interleukin 1β (IL‐1β), and tumor necrosis factor α (TNFα) in response to LPS in vitro, regardless of the structural class of the CCB, suggesting these drugs do target microglia L‐VDCCs. We also found that during microglia activation, microglia upregulate gene expression of the L‐VDCC subunits Cav1.2. Similarly, isradipine was able to reduce microglia activation in vivo. Conclusion Overall these data suggest that the reduced incidence of AD in humans treated with L‐VDCC‐targeting CCBs may be via their modulation of microglia. However, further work is required to understand how these drugs may be utilized as an intervention for AD.