Biomarkers

Target: Ammonia

Ammonia is a colorless alkaline gas with a characteristic sharp smell. Ammonia is one of the most abundant nitrogen-containing compounds in the atmosphere. It is an irritant with a characteristic pungent odor, which is widely used in industry. Inasmuch as ammonia is highly soluble in water and, upon inhalation, is deposited in the upper airways, occupational exposures to ammonia have commonly been associated with sinusitis, upper airway irritation, and eye irritation. Acute exposures to high levels of ammonia have also been associated with diseases of the lower airways and interstitial lung. Ammonia has been shown to be a neurotoxin that predominantly affects astrocytes. Disturbed mitochondrial function and oxidative stress, factors implicated in the induction of the mitochondrial permeability transition, appear to be involved in the mechanism of ammonia neurotoxicity. Ammonia is formed in nearly all tissues and organs of the vertebrate organism; it is the most common endogenous neurotoxic compounds. Ammonia can affect the glutamatergic and GABAergic neuronal systems, the two prevailing neuronal systems of the cortical structures. Ammonia is well recognized to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. The gut produces ammonia which is metabolized in the liver and almost all organ systems are involved in ammonia metabolism. Colonic bacteria produce ammonia by splitting urea and other amino acids, however this does not explain hyperammonemia and hepatic encephalopathy. The alternative explanation is that hyperammonemia is the result of intestinal breakdown of amino acids, especially glutamine. The intestines have significant glutaminase activity, predominantly located in the enterocytes. On the other hand, this organ has only a little glutamine synthetase activity, making it a major glutamine-consuming organ. In addition to the intestine, the kidney is an important source of blood ammonia in patients with liver disease. Ammonia is also taken up by the muscle and brain in hepatic coma, and there is confirmation that ammonia is metabolized in muscle. The excessive formation of ammonia in the brains of Alzheimer's disease patients has been demonstrated, and it has been shown that some Alzheimer's disease patients exhibit elevated blood ammonia concentrations. Ammonia is the most important natural modulator of lysosomal protein processing: there is evidence for the involvement of aberrant lysosomal processing of beta-amyloid precursor protein (beta-APP) in the formation of amyloid deposits. Inflammatory processes and activation of microglia are widely believed to be implicated in the pathology of Alzheimer's disease. Ammonia is able to affect the characteristic functions of microglia, such as endocytosis, and cytokine production. Based on these facts, an ammonia-based hypothesis for Alzheimer's disease has been suggested (PMID: 17006913, 16167195, 15377862, 15369278, 12020619).↵