Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (K 2.1) channels in endothelium of mouse cerebral arteries.

BACKGROUND AND PURPOSE

Inward rectifier potassium (K ) channels are key effectors of vasodilatation in neurovascular coupling (NVC). K channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC-K channel function, but whether oxidative stress or inflammation explains this impairment remains elusive.

EXPERIMENTAL APPROACH

We evaluated K channel function in intact and EC-denuded pial arteries of wild-type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid β-induced oxidative stress seen in AD) or a constitutively active form of TGF-β1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti-inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo.

KEY RESULTS

Our findings show that (i) K channel-mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) K channel dysfunction results from K 2.1 subunit impairment; (iii) about 50% of K -induced artery dilatation is mediated by EC-K channels; (iv) oxidative stress and inflammation impair K channel function, which can be restored by antioxidant and anti-inflammatory drugs; and (v) inflammation induces K 2.1 overexpression and impairs NVC in TGF mice.

CONCLUSION AND IMPLICATIONS

Therapies targeting both oxidative stress and inflammation are necessary for full recovery of K 2.1 channel function in cerebrovascular pathology caused by AD and CVD.