Year: 2016
Type: article
Abstract: Microglia and associated neuroinflammation play a significant role in Alzheimer’s disease (AD). The voltage-gated potassium channel Kv1.3 (KCNA3) fine-tunes microglia activation by modulating Ca signaling. Because selective pharmacological targeting of Kv1.3 in microglia in the brain is feasible and safe, we tested the effects of a selective Kv1.3 blocker PAP-1 in models of AD. Human AD brains drawn from the brain repositories of the University of California Davis and the Emory University were used for immunohistochemical analyses of Kv1.3. 5xFAD mice, which harbor three amyloid-β precursor protein (APP) and two presenilin-1 (PS1) mutations resulting in AD-like Aβ amyloidosis and neuroinflammation, were used for behavioral, electrophysiological, biochemical and neuropathological analyses. Kv1.3 immunoreactivities were localized exclusively to microglia in both human and mouse brains and were increased in human AD subjects and 5xFAD mice. Microglial Kv1.3 activity as measured by whole-cell patch-clamp was increased in young and middle-aged 5xFAD mice, but decreased in old (>13 months) 5xFAD mice compared to age- and gender-matched wild-type controls. Aβ oligomers (AβO) were able to enhance microlgial Kv1.3 expression. PAP-1 treatment reduced AβO-induced microglial neurotoxicity in vitro and in vivo. A three-month oral regimen of PAP-1 improved the hippocampus-dependent memory performance and rectified the hippocampal long-term potentiation of 5xFAD mice. Microglial Kv1.3 is a potential therapeutic target and oral dosing of PAP-1 is a promising anti-inflammatory approach for AD.
Source: Alzheimer s & Dementia
Institutions: University of California, Davis, Emory University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2535272252