Brain Mitochondrial KATP Channel Properties in a Rat Model of Amyloid-β Neurotoxicity: Electrophysiological and Molecular Studies

By far, mitochondrial dysfunction considered as a great risk factor for pathogenesis of Alzheimer’s disease, but there is a little evidence toelucidate the underlying mechanisms of how the Aβ affects mitochondrial function. Since the mitochondrial potassium channels play a vital role in several mitochondrial functions such as calcium homeostasis, cytoprotection, and apoptosis, a study was conducted to survey whether the electrophysiological and structure of mitochondrial KATP was altered in a rat model of Aβ toxicity. Materials and Methods: Aβ1–42 (4 μg/μl/side) was injected intracerebroventricularly in male Wistar rats (220-250 g). After 14 days, brains were removed, homogenized and then the mitochondrial inner membranes were extracted to incorporate in to bilayer lipid membrane (BLM). L-α Phosphatidylcholine was extracted from fresh egg yolk used for BLM formation in a 150 μm diameter hole. All recordings were filtered at 1 kHz and stored at a sampling rate of 10 kHz for offline analysis by PClamp10. Western blotting was used to determine the channel structure. Results: In our previous study, single channel recordings revealed a voltage-dependent KATP channel with a slope conductance of 143 ± 7pS in 200 cis/50 trans mM KCl in control groups. Channel gating were blocked by ATP and glibenclamide (characterize this channel as a KATP channel). Interestingly, in this study, we did not observe any channel activities under Aβ1–42 toxicities. In line with electro-pharmacological observation, western blot analysis shown that there is a ~80%, ~50% and ~30% reduction in Kir6.1, SUR2A and SUR2B subunits expression respectively in Aβ toxicity compared to control. Conclusion: We have presented the first evidence of a physical and functional alteration of KATP Kir6.1, SUR2A and SUR2B subunits in brain mitochondrial inner membrane under Aβ1–42 toxicity. Current data may help us find more insights intochannelopathies in Alzheimer disease and to provide different approaches for disease control.