Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with long preclinical phase, typically followed by a slow decline in memory, thinking and reasoning abilities. The underlying pathological processes are not yet fully elucidated, although two main disease hallmarks have been associated with AD pathology: amyloid beta species and neurofibrillary tangles. The plaques are deposits of a protein fragment called beta-amyloid (Aβ), which accumulates in the spaces between neurons. Tangles are twisted fibers of the tau protein, which accumulates inside the cells. AD is not curable, although some treatments to reduce symptoms are available. Currently, there are five AD drugs approved by the U.S. Food and Drug Administration that treat the symptoms of AD - temporarily helping memory and thinking problems. Four are cholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an N-methyl-D-Aspartate (NMDA) receptor antagonist. However, these medications can only temporarily improve memory, quality of life of patients and decrease burden for caregivers. Among the causes of the disease, the "inflammation hypothesis" of AD has emerged in the recent years and it is based on findings on cells of the immune response in central nervous system (CNS). It is known that microglia and astrocytes initiate the immune response in the brain after exposure to pathogens. However, when the activation of the immune system is permanent, a condition called neuroinflammation is established, causing damage to CNS neurons. In AD, a chronic neuroinflammatory state with release of proinflammatory cytokines has been observed, which appears to be correlated to the constant accumulation of Aβ within neurons. It is not clear whether the chronic neuroinflammation precedes the onset of the disease or is a consequence of Aβ accumulation. It has been hypothesized that the chronic neuroinflammation observed in AD is associated with an alteration of the balance of gut microbiota, a phenomenon known as dysbiosis, which can negatively affect neuronal activity (Jiang et al.,
2017). Gut microbiota are able to influence brain activity through either immune/humoral activity or the vagus nerve that connects intestinal neurons with those of the CNS. In this way, disturbance in gut microbiota can cause brain dysfunctions. The term Microbiota-Gut-Brain Axis has been introduced to describe this interaction, but the association between gut microbiota and AD is also related to the role of inflammation in the development and course of AD. Some theories have been developed to explain the role of gut microbiota in inducing a chronic neuroinflammation in AD. The most important are: (1) a direct microbial infection inducing a neuroinflammatory state in the brain of AD patients; (2) an age-related dysbiosis", which hypothesizes that AD arises during the process of aging of the immune system; (3) an antimicrobial protection hypothesis, which suggests that the accumulation of Aβ in the brain represents an immune response to the accumulation of harmful bacteria; and (4) the hygiene hypothesis of AD, which indicates in an excessive sanitation in early life the cause of late impaired function of the immune system. In a recent publication, we examined in detail the scientific evidence for the role of gut microbiota in AD and the possible effects of compounds that alter its composition, such as pre- and probiotics and antibiotics.