The Role of Microbial Immune Responses in Alzheimer’s Disease

Animal models of Alzheimer’s disease (AD) recapitulate the severe amyloidosis and neuroinflammation that is evident in the human disease. While it long has been assumed that inflammation associated with amyloid deposition reflects the activation of astrocytes and microglia into proinflammatory M1 states in response to injury, there is a paucity of information regarding the potential role of peripheral tissues and, more importantly, the microbiota in regulating innate immunity that in turn leads to CNS dysfunction. The notion that the commensal intestinal microbiota can influence brain function has at least one clear clinical origin: the observation that orally administered antibiotics can reverse encephalopathy in patients with decompensated liver disease (Schiano, 2010). Furthermore, psychiatric disorders frequently coexist with common gastrointestinal conditions, such as irritable bowel syndrome (IBS) that also are associated with disturbances of the intestinal microbiota. Emerging animal-based research has extended the idea of microbiota–brain interactions to other psychiatric disorders, as well as to immunologically mediated neuro­logical conditions such as multiple sclerosis (MS) and to the exciting area of early brain development that has implications for autism spectrum disorders. For example, during vaginal deliv­ery, the gastrointestinal tract of the newborn is colonized by the bacteria in the lower birth canal and perineum of the mother; therefore, the microbiota of infants delivered by Caesarean section differs from that of infants delivered through the genital tract. Studies in rats indicate that rats delivered at term by Caesarean section exhibit alterations (compared with rats delivered vaginally) in the prepubertal development of the prefrontal cortex and hippocampus (Juarez et al., 2008). A study on human neonates showed that the pattern of electrical activity in the brain is less complex in neonates born by Caesarean section than in age-matched neonates born by vaginal delivery (Kim et al., 2003). These latter results raise the possibility that different colonization patterns influence early postnatal brain development and also have longer-term consequences. Thus, this rapidly emerging field has the potential not only to increase our understanding of a broad spectrum of human disease, but also to generate novel therapies for these conditions based on the identification of mechanisms underlying microorganism-host interactions.