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Oxygen Tissue Levels as an Effectively Modifiable Factor in Alzheimer’s Disease Improvement

Written By

Arturo Solís Herrera

Submitted: 15 June 2022 Reviewed: 06 July 2022 Published: 29 July 2022

DOI: 10.5772/intechopen.106331

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Abstract

Despite the advance in biochemistry, there are two substantial errors that have remained for at least two centuries. One is that oxygen from the atmosphere passes through the lungs and reaches the bloodstream, which distributes it throughout the body. Another major mistake is the belief that such oxygen is used by the cell to obtain energy, by combining it with glucose. Since the late nineteenth century, it began to be published that the gas exchange in the lungs cannot be explained by diffusion. Even Christian Bohr suggested that it looked like a cellular secretion. But despite experimental evidence to the contrary and based only on theoretical models, the dogma that our body takes the oxygen it contains inside from the air around it has been perpetuated to this day. The oxygen levels contained in the human body are high, close to 99%, and the atmosphere only contains between 19 and 21%. The hypothesis that there is a supposed oxygen concentrating mechanism has not been experimentally proven to date, after almost two centuries. The mistaken belief, even among neurologists, that our body takes oxygen from the atmosphere is widespread, even though there is no experimental basis to support it, just theoretical models. Our finding that the human body can take oxygen from the water it contains, not from the air around it, like plants, comes to mark a before and after in biology in general, and the CNS is no exception. Therefore, establishing the true origin of the oxygen present within our body and brain will allow us to better understand the physio pathogenesis of neurodegenerative diseases.

Keywords

  • oxygen
  • AD
  • water
  • ventricles
  • volume
  • CSF

1. Introduction

Current medicine is based in an important way on two wrong assumptions: (1) The oxygen present inside the body comes from the atmosphere because theoretically it can cross the thin alveolar membrane and reach the bloodstream, which distributes it to all the cells of the body [1]. (2) Oxygen from the atmosphere is used by cells to produce energy, by combining it with glucose or its intermediate metabolites, something like graduated combustion [2].

However, the passage from atmospheric oxygen to the blood circulation through the pulmonary alveoli has not been demonstrated so far in addition to going against the behavior of gases. Therefore, the first error gives rise to a second mistake: the combination of oxygen with glucose to produce energy.

Both concepts are entirely theoretical, and concepts so far-fetched and tangled that it is not possible to contrast them experimentally. Thereby, we do not have definitive and complete answers to important questions behind the simple picture that in mammals, oxygen is extracted from the atmospheric air in the lungs and carried by the bloodstream through the circulation to the tissue, where it is utilized mainly within the mitochondria [3].

The brain is an organ whose normal function depends critically on an uninterrupted delivery of oxygen. Unlike skeletal muscle that can survive for hours without oxygen, brain cells show irreversible damage within minutes from the onset of oxygen deficiency. Thus, theoretical studies (they cannot be otherwise) have special importance for understanding how oxygen is distributed in different structures of the brain under normal and hypoxic conditions [4].

Theoretical work on oxygen transport in the brain began with applications of the Krogh Equation [5] and the extension of the Krogh model to hexagonal space-filling tissue cylinders [6]. A systematic analysis of oxygen transport in the brain with the Krogh model was performed by Reneau and his coworkers [7]. Note that they all are theoretical in their entirety (Figure 1).

Figure 1.

Krogh Cylinder (simplified). The concepts handled by Krogh’s models are so complex and far-fetched that they cannot even be experimentally contrasted. I quote few names: Anoxic lethal corner, O2 radial vectors, capillary radius, capillary X-section, cylinder radius, cylinder X-section, anoxic tissue, axial kick, augmented O2 radial vectors, OPF range, average ptO2, hypercapnic lethal corner, normal intracapillary blood flow velocity.

However, the architecture of the capillary network in the brain does not provide support for the Krogh model [8]. The oxygen consumption rate within the neuron is about ten times higher than in the glial cells, and that has a significant effect on oxygen distribution [9]. There is experimental evidence that significant precapillary loss of oxygen occurs in the cerebral circulation [10].

The problem of oxygen loading in the blood capillaries of the lung is, in a sense, inverse to the problem of oxygen unloading in other tissues. Therefore, for a better understanding of oxygen transport, simultaneous analysis of oxygen and carbon dioxide transport is necessary [11].

At present none of the models of oxygen transport (including Krogh’s model) has been carefully tested against experimental data. The main reason appears to be the lack of accurate measurements of oxygen tension and hemoglobin saturation in vivo with the spatial resolution necessary for the validation of distributed transport models [12].

The mathematical and statistical models that are used to try to explain biological processes, such as gas exchange, usually do not work because, in biology, the variables are continuous random (nonlinear behavior). When the phenomena to be studied are discrete variables (linear behavior), mathematical models work better, as is the case of predicting the production of a factory, the possibility that manufacturing processes produce wrong parts, etc. But this is not the case in biology, because the values that variables can take change from one moment to the next, and it is not understood why.

Hence, Krogh’s equation of 1919, which is a mathematical (imaginary) model, has been added to other equations by different authors until reaching about 120 equations (Figure 2).

Figure 2.

A sample of the first 32 equations of already 120 described that have been implemented with the aim of building Krogh’s acceptable theoretical (imaginary) model about oxygen transportation theory.

The result is a set of mathematical operations so far-fetched and tangled that it is impossible to contrast them in the laboratory. And we are talking about Krogh or Krogh–Erlang equation, which has been the basis of most physiological estimates for the last 70 years.

Some models assumed that tissue is spatially homogeneous. Tissue consists of cells and extracellular spaces. Further, there are intracellular heterogeneities, for example, those caused by discrete oxygen consumption by mitochondria. These heterogeneities may affect the distribution of oxygen in the tissue. Theoretically, inside the cell, oxygen is consumed almost exclusively within mitochondria [13].

It has been proposed that oxygen is transported from blood to mitochondria along channels of high solubility; the endoplasmic reticulum could serve to channel oxygen [14]. The cytosol is largely free of oxygen because of its low solubility. However, theoretical and experimental validation of this hypothesis (1980) remains to be done. It is frustrating that the bases of oxygen transport and gas exchange, which constitute the foundations of the clinic, cannot be experimentally contrasted because of how tangled they are.

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2. Oxygen transportation (if any) and brain

Supposedly, the brain is an organ whose normal function depends critically on an uninterrupted delivery of oxygen. However, the element of real value for cell metabolism is hydrogen and it is produced at the same time than oxygen; both come from water dissociation. It is relatively simple to show that melanin dissociates the molecule from water, generating both molecular hydrogen and oxygen (Figures 3 and 4). It is difficult to measure the levels of molecular hydrogen inside the cells; it is more practical to determine molecular oxygen levels. Thereby, oxygen levels are indirect markers of hydrogen levels because both elements come from the dissociation of water that occurs inside the cell, thanks to melanin and other pigments. It can be said that both hydrogen and oxygen are produced at the same time and in the same place.

Figure 3.

The melanin in the banana peel, illuminated with polychromatic (white) light.

Figure 4.

When the same specimen of Figure 3 is illuminated with monochromatic light in the ultraviolet light range (10–400 nm), a distinctive fluorescence appears. Due to the presence of hydrogen that comes from the dissociation of water by melanin, oxygen does not fluoresce.

Unlike skeletal muscle that can survive for hours without oxygen, brain cells show irreversible damage within minutes from the onset of oxygen deficiency that reflects low level of hydrogen by impairment of water dissociation mechanisms.

Theoretical work on oxygen transport in the brain began with applications of the Krogh Equation [5] and the extension of the Krogh model to hexagonal space-filling tissue cylinders [6]. A systematic analysis of oxygen transport in the brain with the Krogh model using the numerical finite-difference method to obtain solutions to steady and unsteady problems of physiological importance was performed in 1967 [15]. As expected, the architecture of the capillary network in the brain does not provide support for the Krogh model. Thereby, other models have been formulated trying to reflect the heterogeneity of capillary architecture and hemodynamics [8].

It is interesting that the oxygen consumption rate within the neuron is about ten times higher than in the glial cells [9], but this finding tells us that the intensity of water dissociation is 10 times more in glial cells than in neurons, because the neuron or any cells do not consume oxygen to produce energy, because the power requirements of the cells are based on the hydrogen that is released when water is dissociated, and molecular hydrogen (H2) is the element that carries energy, not only in cells but throughout the universe. In AD patients, there is chronic hypoxia that, in turn, indicates a chronic lack of hydrogen, and therefore a generalized lack of energy. The source of the problem is that the brain tissues are not able to dissociate the water at the necessary rate, and then the liquid water accumulates characteristically in the ventricles.

In most studies of oxygen transport, the governing differential equations are solved numerically by a discretization method, either finite difference or finite element, which is typical of imaginary models and that can hardly become a representation of reality due, among other things, that biological processes are made up of continuous random variables.

There is experimental evidence that significant precapillary loss of oxygen occurs in the cerebral circulation [16], which for us means that water dissociation decreases in that region normally.

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3. The role of oxygen in neurodegenerative diseases

So far, Alzheimer’s disease (AD) is considered an incurable neurodegenerative disease [17]. Recent studies suggest that the neurobiology of AD pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. These early changes affect several key metabolic processes related to glucose uptake and insulin signaling, cellular energy homeostasis, mitochondrial biogenesis, and increased Tau phosphorylation by kinase molecules, such as mTOR and Cdk5 [18].

The condition involves a progressive deterioration in memory, cognition, and mobility. Numerous studies have demonstrated a critical role of dysregulated glucose metabolism in its pathogenesis. The already described metabolic alterations in the aging brain and AD-related metabolic deficits are associated with glucose metabolism dysregulation, glycolysis dysfunction, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) deficits, and pentose phosphate pathway impairment. There are numerous biochemical alterations that occur simultaneously.

AD pathophysiology is extremely complex and heterogeneous, entailing accumulation of senile plaques caused by abnormal amyloid β (Aβ) metabolism, and neurofibrillary tangles caused by tau hyperphosphorylation. The cerebrovascular system is seriously damaged, including the disturbance of the blood–brain barrier (BBB) and cerebral amyloid angiopathy [19]. Functional failures and anatomical changes are multiple and varied, as they do not follow a definite pattern, which is compatible with energy failure.

Supposedly, increased levels of reactive oxygen species (ROS) induce the transcription of pro-inflammatory genes and the release of cytokines (e.g., interleukin-1β [IL-1β], IL-6, and tumor necrosis factor-alpha [TNF-α]) and chemokines that cause neuroinflammation. Furthermore, reactive microglia and astrocytes and other pathological events also contribute to the dysfunction and deprivation of synapses and, ultimately, neuronal death [20]. It seems that the cells lose for some reason, the complex order that characterizes them even though neurons have done their job for millions of years, millions of times, every day.

It could be said that both functional and anatomical failure of the brain’s human body is widespread. And in any system, when the faults are so extensive, one must first think about energy [21].

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4. Oxygen as a biomarker of energy levels

The brain consumes the greatest amount of energy of all the organs in the body, except the retina photoreceptor layer [22]. There is an age-related decrease in glucose utilization in most human brains [23].

However, it is conflicting that oxygen consumption is studied by determining the levels of mitochondrial nitric oxide synthase when synthases are enzymes that do not use ATP as an energy source to carry out their function [24].

The pathological metabolic alterations in aging (e.g., cerebral glucose hypometabolism) are early and consistent events in the progression of AD. Glucose, the main transportation form of carbohydrate in our blood, is also the crucial and primary energy substrate for the brain under physiological conditions [25]. Glucose is the universal precursor of any organic molecule, but it cannot provide the energy that its own metabolism requires [26], thereby, the prevalent dogma about glucose as source of biomass and energy at the same time now is broken down into thousands of pieces after our discovery of the unexpected capacity of the human body to take oxygen from the water molecule, like plants.

Alternative substrates, such as glycogen, ketone bodies, and amino acids, are also important, but only as a source of carbon chains that our body uses to build up other organic molecules. Energy hypometabolism, particularly a decline in glucose metabolism, is one of the earliest and most common anomalies observed in patients with AD [27], but glucose should not be considered an energy substrate, but a metabolic intermediate that requires energy from the dissociation of water.

Statistically, our body begins to lose its capacity to take oxygen from water at 26 years old, at approximately 10% rate each decade; and after the fifties, goes into free fall. This is an important date because the decline in glucose use capacity by the cells observed with aging is congruous with the loss of capacity to take oxygen from water. Remember that glucose metabolism requires oxygen, this is: energy.

Despite those, the main intracellular energy metabolism pathways, (theoretical all of them) occurring in our brains are necessarily complicated and include anaerobic glycolysis and the pentose phosphate pathway (PPP) in the cytoplasm, as well as oxidative phosphorylation (OXPHOS) in mitochondria and the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle and Krebs cycle) [28], these neuronal metabolic pathways are controversial in circa 98% like in other cells and tissues [29]. CNS biology is no exception to collective mistakes in regards to the wrong double role of glucose as a source of biomass and energy at the same time. No way.

Metabolic processes are regulated by a series of key enzymes. Indeed, a growing body of evidence suggests the presence of organic impairment of mitochondria [30] and damage to related metabolic enzymes [31]. In addition, oxygen and glucose metabolic rates are drastically changed in many neurodegenerative diseases, including AD due to marked alterations in the glycolytic pathway and TCA cycle [32]. Again, it seems like a generalized failure.

The picture is a metabolic dysregulation in many senses, it is a typical generalized fault. Traditionally, glucose is metabolized to ATP, an unstable high-energy compound. An entirely theoretical dogma. If we analyze the energy required by all the components that are described for glucose to end up in ATP, there would be nothing left for the cell.

Researchers are determined to explain the flow of energy where there is none, because it is not possible to obtain more energy than the molecule as is the case of glucose. They forget that the energy needs of the cell are constant, day and night. So, our discovery erases everything theoretically, because when the cell obtains oxygen from water, at the same time it obtains energy, which is transported by hydrogen, the main carrier of energy in the entire universe.

So, oxygen is important for life, it is fundamental; but not in the role that had been assigned to it —combustion of glucose—but to form the cellular scaffolding, of tissues, organs, and systems, which optimizes the use of energy that comes from the sun, but not through food as had been believed to date, but our body is able to capture it directly, like plants.

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5. The oxygen inside our body (and brain) does not come from the atmosphere

There is a deeply rooted dogma that oxygen from the atmosphere passes through lung tissues by simple diffusion and reaches the bloodstream, which distributes them to all cells of the body. But from the mid-nineteenth and early twentieth centuries, intense controversy was generated due to the works of Carl Ludwig, Christian Bohr, Haldane, and others, who sought experimentally, both in man and other lung animals, the mechanism by which the %SpO2 rises to more than 95%. And not only did they not find it, but they realized that diffusion alone (the theory in vogue) could not explain the gas exchange in the lungs [33].

So, if the source of oxygen in the body is the water it contains, then the water of the cerebral-spinal fluid (CSF) acquires unusual importance. Well, it is the source of oxygen and hydrogen in the CNS.

Our finding that the human body has several molecules capable of transforming light power into chemical energy, through the dissociation of water [34], like plants, is a disruptive discovery.

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6. Conclusion

It is not known if oxygen is transported in blood mainly by pure convection. The roles of diffusion and chemical kinetics are not defined yet. The importance of the resistances to oxygen transport by various membranes is unknown. It is uncertain that oxygen cross cell membranes (red blood cells, endothelial cell, and parenchymal cell) by pure diffusion or if it is facilitated by a carrier. The mechanisms of oxygen transport inside the cells are not known. It is not possible, so far, to identify active transport in oxygen delivery. It is unknown the supposed main site of oxygen exchange between the blood and tissue (arterioles, capillaries, or venules). Sadly, we do not have definitive and conclusive answers to these fundamental questions due to the experiments that are required to do so, in regards to Krogh’s model technically are not possible to date. A clear understanding of the physical mechanisms of oxygen transport throughout the pathway is a way beyond, starting because oxygen does not come from the atmosphere, and therefore is not transported.

Krogh laid the wrong foundation for the theory of oxygen transport to the tissue [35]. He proposed, without experimental foundations and based only on theoretical (imaginary) models, that oxygen is transported in the tissue by passive diffusion driven by gradients of oxygen tension (PO2). Krogh tissue cylinder or simply Krogh’s model is a simple geometrical model of the elementary tissue unit supplied by a single capillary. Krogh formulated a differential equation governing oxygen diffusion and uptake in the tissue cylinder assisted by Erlang, a mathematician.

The solution to this equation theoretically expresses oxygen tension in the tissue as a function of spatial position within the tissue cylinder. This simple assumption so-called Krogh equation, known as the Krogh or Krogh–Erlang equation, has been the basis of most physiological estimates for the last 70 years, but now it breaks into a thousand pieces thanks to the discovery of the unsuspected ability of the human body to take oxygen from the water it contains [36], just as plants do.

Only a decade ago, the picture of oxygen delivery from cells to the sites of oxygen consumption, even though it became unnecessarily complex, had not differed qualitatively from that described by Krogh in 1919. In the past 10 years, theoretical Krogh’s concept of radial PO2 gradients in the tissue from the capillary has undergone drastic changes and has all but reversed. Indeed, it is now proposed, in yet another attempt to explain to exploit with mathematical models a theory that cannot be tested experimentally, that the dominant PO2 gradients on the pathway from hemoglobin to mitochondria occur not in the tissue but inside the vessels. These new concepts, also entirely theoretical; require further and highly complex experimental validation and new theoretical developments. However, if they are valid, then much of our understanding of oxygen transport to tissue will have to be reassessed.

In any case, the models based on the Krogh theorems and the recent trend of non-Krogh models will continue to be futile, as they try to explain how oxygen from the atmosphere passes through the lungs and reaches the bloodstream to be distributed throughout the body.

The discovery of the human body’s unsuspected ability to take oxygen from the water contained within cells, such as plants, constitutes the beginning of a new era in the study and treatment of neurodegenerative diseases such as Alzheimer’s.

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Acknowledgments

This work was supported by Human Photosynthesis™ Research Centre. Aguascalientes 20000, México.

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Written By

Arturo Solís Herrera

Submitted: 15 June 2022 Reviewed: 06 July 2022 Published: 29 July 2022