A new mechanism for amyloid-β induction of iNOS: vitamin D-VDR pathway disruption.

The inflammatory process in Alzheimer's disease (AD) has been suggested to include oxidative and nitrosative damage caused by elevated levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Here, we investigated iNOS expression in cortical neurons following amyloid-β (Aβ) treatment, vitamin D treatment, Aβ combined with vitamin D treatment, and vitamin D signaling disruption via silencing of nuclear (vitamin D receptor-VDR) or membrane vitamin D (1,25-MARRS) receptors. We observed that Aβ induced iNOS expression. Vitamin D prevented Aβ-induced cytotoxicity and iNOS upregulation in cortical neurons. Our silencing experiments suggest that vitamin D regulates iNOS via VDR, not 1,25-MARRS, in cortical neurons. Consequently, VDR absence induces iNOS expression in either the absence or presence of Aβ. While our previous work demonstrates that Aβ pathology includes VDR suppression, our present work demonstrates that Aβ induces iNOS and that this effect is mediated via disruption of the vitamin D-VDR pathway. These data suggest the existence of crosstalk between Aβ pathology and VDR. Thus, vitamin D supplementation should be considered a candidate in both the treatment and prevention of AD.