Potassium Channel Kv1.3 Is Highly Expressed by Microglia in Human Alzheimer's Disease

Abstract

Recent genetic studies suggest a central role for innate immunity in Alzheimer’s disease (AD) pathogenesis, wherein microglia orchestrate neuroinflammation. Kv1.3, a voltage-gated potassium channel of therapeutic relevance in autoimmunity, is upregulated by activated microglia and mediates amyloid-mediated microglial priming and reactive oxygen species production in vitro. We hypothesized that Kv1.3 channel expression is increased in human AD brain tissue. In a blinded postmortem immunohistochemical semi-quantitative analysis performed on ten AD patients and ten non-disease controls, we observed a significantly higher Kv1.3 staining intensity (p = 0.03) and Kv1.3-positive cell density (p = 0.03) in the frontal cortex of AD brains, compared to controls. This paralleled an increased number of Iba1-positive microglia in AD brains. Kv1.3-positive cells had microglial morphology and were associated with amyloid-β plaques. In immunofluorescence studies, Kv1.3 channels co-localized primarily with Iba1 but not with astrocyte marker GFAP, confirming that elevated Kv1.3 expression is limited to microglia. Higher Kv1.3 expression in AD brains was also confirmed by western blot analysis. Our findings support that Kv1.3 channels are biologically relevant and microglia-specific targets in human AD.

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

“…10). Because CFZ selectively inhibits Kv1.3 function (Ren et al, 2008), and Kv1.3 channels are considered principal regulators of microglial cell reactivity (Rangaraju et al, 2015), we focused on microglial labeling differences. In normal untreated callosal cultures, Kv1.3 expression was evident for each microglial morphology present, even in cells with lower IBA1 signal (Fig.…”

“…Our observations that postinjury axonal function can be altered by Kv1.3 manipulation, and that white matter microglia potentially mediate this effect through Kv1.3 regulation of inflammatory molecules, are supported by Kv1.3 studies using models of neurodegeneration and epilepsy. Postmortem analysis of Alzheimer’s disease patients revealed significantly higher levels of Kv1.3 channels co-localized with microglial cells, but not with astrocytes (Rangaraju et al, 2015). Kv1.3 was shown to be highly expressed on inflammatory leukocyte infiltrates in brains from multiple sclerosis patients, and Kv1.3 was elevated in both gray and white matter (Rus et al, 2005).…”

“…Indeed, the CAP recordings in this study showed the unmyelinated signal underwent the greater degree of post-traumatic suppression, and was most protected by CFZ treatment, relative to the myelinated signal. Kv1.3 is a component of the outward rectifier currents in microglia (Khanna et al, 2001; Pannasch et al, 2006), and these channels are key regulators of microglial function (Rangaraju et al, 2015). Prior experiments with primary cortical microglia showed that blocking Kv1.3 channels markedly diminished microglial migration to areas of cellular debris (Nutile-McMenemy et al, 2007).…”

Potassium channel expression and function in microglia: Plasticity and possible species variations

“…28 Kir channels are also expressed, but the noteworthy finding is the lack of K V 1.3 expression and presence of K Ca 1.1 instead. What is particularly surprising about the missing functional K V 1.3 expression, is that several immunohistochemistry studies have previously shown strong K V 1.3 specific staining on activated microglia in human ischemic infarcts, 22 microglia surrounding amyloid-plaques in Alzheimer disease, 41 as well as on cells with a glia morphology in active multiple sclerosis lesions. 42 Combined with our finding that cultured prenatal human microglia clearly express K V 1.3, and that microglia exhibit such a pronounced and stimulidependent expression plasticity, a reasonable assumption is that the "adult epilepsy microglia phenotype" carries a unique set of K C channels dictated by their specific aging and/or epilepsy/medication history.…”

Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

“…DAB-peroxidase immunohistochemistry was performed using antibodies directed against alpha synuclein (phospho S129) (1:500; Abcam, Melbourne, Australia) [20] and p62 (1:100; BD Biosciences, CA, USA) for macrophagy [21]. The doublelabelled fluorescent immunohistochemistry was performed using antibodies directed against Iba1 (1:100; Abcam, Melbourne, Australia) for microglia [22] and Human Leukocyte Antigen -antigen D Related (HLA-DR, 1:200, Dako Corporation, Carpinteria, CA, USA) for activated microglia [23]. The experimental procedures have been described previously [3,19].…”