Ammonia and Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Behavioural, cognitive and memory dysfunctions are characteristic symptoms of AD. The formation of amyloid plaques is currently considered as the key event of AD. Other histological hallmarks of the disease are the formation of fibrillary tangles, astrocytosis, and loss of certain neuronal systems in cortical areas of the brain. A great number of possible aetiologic and pathogenetic factors of AD have been published in the course of the last two decades. Among the toxic factors, which have been considered to contribute to the symptoms and progression of AD, ammonia deserves special interest for the following reasons: (a) Ammonia is formed in nearly all tissues and organs of the vertebrate organism; it is the most common endogenous neurotoxic compounds. Its effects on glutamatergic and GABAergic neuronal systems, the two prevailing neuronal systems of the cortical structures, are known for many years. (b) The impairment of ammonia detoxification invariably leads to severe pathology. Several symptoms and histologic aberrations of hepatic encephalopathy (HE), of which ammonia has been recognised as a pathogenetic factor, resemble those of AD. (c) The excessive formation of ammonia in the brains of AD patients has been demonstrated, and it has been shown that some AD patients exhibit elevated blood ammonia concentrations. (d) There is evidence for the involvement of aberrant lysosomal processing of beta-amyloid precursor protein (beta-APP) in the formation of amyloid deposits. Ammonia is the most important natural modulator of lysosomal protein processing. (e) Inflammatory processes and activation of microglia are widely believed to be implicated in the pathology of AD. Ammonia is able to affect the characteristic functions of microglia, such as endocytosis, and cytokine production. Based on these facts, an ammonia hypothesis of AD has first been suggested in 1993. In the present review old and new observations are discussed, which are in support of the notion that ammonia is a factor able to produce symptoms of AD and to affect the progression of the disease.