Author(s): Pierre A. Denis
The present article focuses on the model metabolic stress in AD. This novel model proposes that nitrogen nanobubbles, having invaded the brain interstitial fluid from the blood through glucose transporter-1 (GLUT-1), cause the pressure to increase in the close surroundings, before being embedded in amyloid-β fibrils in the form of cerebral amyloid angiopathy that fixes the pollutant. Following the huge increase in the surrounding pressure, molecular oxygen, the regular form of oxygen in a low PO2 solute, gather into oxygen nanobubbles, leading to various normal responses, albeit damaging. Therefore, nanobubbles trigger the NADPH oxidase-NO antibubble biomachinery that produces superoxide and peroxynitrite. The high NADPH/NADP+ turnover is supported by the pentose phosphate pathway. Oxygen nanobubbles in mitochondria could explain the impairment of complexes I and IV. The amyloid percolation well model might resolve the issue of the coimmunoprecipitation of Aβ with the latter complexes, Aβ stabilizing oxygen bubbles, as it might stabilize nitrogen bubbles in the ISF. The permeabilization of the mitochondrial membrane by unspecific pores fixes the overpressure on the mitochondria. The bubble-induced crowding of the respiratory chains causes energy depletion due to the disruption of oxidative phosphorylation, leading to the irreversible injury of respiration, also known as Warburg effect. The main consequence is a deficit in the cholinergic system. Last, the peroxynitrite/CO2 system is deciphered as a CO2 antibubble buffer, rescuing the impaired carbonic anhydrase in AD. Sometimes, CO2 is not released from peroxynitrite, and then produces nitrite anions and carbonyl radicals after intermediate reactions. These respectively lead to the nitrotyrosination and carbonylation of numerous proteins but hold the cells free from a CO2 bubble-induced disruption of the cytoplasmic and the mitochondrial membranes. The AD Gas Model paves the way to new approaches to address the pathophysiology of the most devastating brain disease in human beings.
