Alzheimer's disease: A gas model. The NADPH oxidase-Nitric Oxide system as an antibubble biomachinery

Alzheimer's disease (AD) is a neurodegenerative disease of unknown origin. The pathological lesions that define AD would be linked to the insidious accumulation of nitrogen, having invaded the brain interstitial fluid (ISF) from the blood via the physiological cycling pool of vascular glucose transporters (GLUT-1). According to this hypothesis, the nitrogen nanobubbles, being chemically inert and actually indestructible for human beings, can not escape from the ISF anymore. They would exert a huge and deleterious pressure against cellular components, especially in microglia and in astrocytes. They could enhance the existing cell oxygen anisotropy, which might enhance the natural bubble nucleation of O2-2O2 in cells or in mitochondria. Indeed, with the help of a new symbolic representation for gas nuclei in chemical reactions, the NADPH oxidase-NO system is identified for the first time, as an antibubble biomachinery, able to break O2-2O2 bubbles up as it releases superoxide O2-. Superoxide is considered as a quantum bubble, which collapses through the reactivity of the gaseous NO radical. Their combination in soluble peroxinitrite provides the change from one state of matter to another, avoiding any risk of a bubble enlargement, and finally avoiding the risk of enzyme crowding or of a bulk pressure variation. However, a bubble is expected to entrap Nitric Oxide (NO), which leads theoretically to a decrease in its bioavailability, and is expected to trigger a guanylyl-cyclase-mediated inflammatory cascade, that could explain the inflammation in AD. In vitro, any increase in the hydrostatic pressure has already been linked to the microtubule disorganization. The amyloid deposits, also known as senile plaques, would behave as a sponge toward ISF nitrogen; Aβ is considered as a foam-stabilizing agent. By taking the shape of cerebral amyloid angiopathy, the amyloid could confine the nitrogen leak from the blood, and progressively insulate the Blood-Brain Barrier against the pollutant. All these theoretical features finally lead to the death of the neurons.The comprehensive statement of the theoretical pro-inflammatory action of inert gases is a real upheaval for the whole medicine.

Graphical abstractThe AD gas model proposes that a nitrogen leak from the blood invades the brain interstitial fluid (ISF) through the vascular endothelium (symbolized as a double membrane). The foam is expected to increase the pressure in the ISF (see red arrows) and to enhance the oxygen anisotropy in the neighbouring cells. In these cells, the constitutive antibubble biomachinery becomes overloaded, which result in an increased formation of Reactive Oxygen Species (depicted as ONOO). The decrease in the NO bioavailability triggers a guanylyl cyclase-mediated inflammation (see GC). Amyloid is thought as a buffer zone toward nitrogen.Download high-res image (228KB)Download full-size image